1,3-dihydro-2H-indol-2-one derivative

ABSTRACT

A 1,3-dihydro-2H-indol-2-one derivative expressed by Formula 1 (wherein R 1  is a halogen atom, a C 1  to C 4  alkyl group, etc., and R 2  is a hydrogen atom, a halogen atom, etc., or R 2  is in the 6-position of the indol-2-one and R 1  and R 2  join together to form a C 3  to C 6  alkylene group, R 3  is a halogen atom, a hydroxyl group, etc., and R 4  is a hydrogen atom, a halogen atom, a C 1  to C 4  alkyl group, etc., or R 4  is in the 3-position of the phenyl and R 3  and R 4  join together to form a methylenedioxy group, R 5  is a hydrogen atom or a fluorine atom, R 6  is an ethylamino group, a dimethylamino group, etc., R 7  is a C 1  to C 4  alkoxy group, and R 8  is a C 1  to C 4  alkoxy group), or a pharmaceutically acceptable salt of this derivative. This is a novel compound that has antagonistic activity against an aruginine-vasopressin V1 b  receptor.

TECHNICAL FIELD

This invention relates to a 1,3-dihydro-2H-indol-2-one derivative, amethod for manufacturing thereof, and intermediates thereof, and moreparticularly relates to a 1,3-dihydro-2H-indol-2-one derivative that hasantagonistic activity against an arginine-vasopressin V1b receptor andis useful in preventing or treating diseases such as depression,anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease,eating disorders, hypertension, gastrointestinal diseases, drugdependence, epilepsy, cerebral infarction, cerebral ischemia, cerebraledema, head trauma, inflammation, immunological diseases, and alopecia,a method for manufacturing thereof, and intermediates thereof.

BACKGROUND ART

Arginine-vasopressin (AVP) is a peptide composed of nine amino acids,which is synthesized mainly in the hypothalamus, and as a posteriorpituitary hormone it is closely related to the regulation of plasmaosmotic pressure, blood pressure, and body fluid level.

Three sub-types of AVP receptor, namely, V1a, V1b, and V2 receptors,have been cloned, and all are known to be “seven transmembranereceptors”. The V2 receptor couples with Gs and increases the cAMPlevel. The V1a receptor couples with Gq/11, promotes PI response,increases intracellular Ca, is expressed in the brain, liver, adrenalgland, vascular smooth muscle, and so on, and is involved in vascularcontraction. Meanwhile, the V1b receptor is similar to the V1a receptorin that it couples with Gq/11 and promotes PI response (Non-PatentDocuments 1 and 2). The V1b receptor is most prevalent in the pituitarygland (expressed in over 90% of ACTH-secreting cells of the anteriorlobe), and has been presumed to be involved in ACTH secretion from theanferior lobe of pituitary by AVP. In addition to being found in thepituitary, the V1b receptor is also found over a wide region of thebrain, and is also prevalent in the raphe nuclei, which are the nucleiof serotonergic neurons, the cerebral cortex, and the olfactory bulb,and parts of the limbic system such as the hippocampus, amygdala, andentorhinal cortex (Non-Patent Documents 3 and 4).

Relationship between the V1b receptor and depression and anxietydisorders has recently been suggested, and the usefulness of a V1breceptor antagonist has been studied. It has been indicated thataggressive behavior is reduced in V1b receptor KO mice (Non-PatentDocument 5). It has also been reported that injection of a V1b receptorantagonist into the septum prolongs the time on open-arms in an elevatedplus maze test (anxiolytic action) (Non-Patent Document 6). Morerecently, a V1b receptor-specific antagonist has been synthesized thatis a systemically administrable 1,3-dihydro-2H-indol-2-one derivative(Non-Patent Documents 1 to 6). Also, 1,3-dihydro-2H-indol-2-onederivatives have been reported exhibit antidepressant and anxiolyticeffects in various animal models (Non-Patent Documents 7 and 8). Thecompound disclosed in Patent Document 1 exhibits high affinity (1 to4×10⁻⁹ mol/L) and selectivity towards a V1b receptor, and isantagonistic to AVP, AVP+CRF, and restraint stress-induced ACTHincrease.

However, Patent Documents 1 to 6 do not disclose a compound which afluorine atom has been introduced into a pyrrolidine ring bonded to the3-position of 1,3-dihydro-2H-indol-2-one.

Non-Patent Document 1: Sugimoto T., Kawashima G, J. Biol. Chem., 269,27088-27092, 1994.

Non-Patent Document 2: Lolait S., Brownstein M., PNAS, 92, 6783-6787,1995.

Non-Patent Document 3: Vaccari C., Ostrowski N., Endocrinology, 139,5015-5033, 1998.

Non-Patent Document 4: Hernando F., Burbach J., Endocrinology, 142,1659-1668, 2001.

Non-Patent Document 5: Wersinger S. R., Toung W. S., Mol. Psychiatry, 7,975-984, 2002.

Non-Patent Document 6: Liebsch G., Engelmann M., Neurosci. Lett., 217,101-104, 1996.

Non-Patent Document 7: Gal C. S., Le Fur G., 300, 1122-1130, 2002.

Non-Patent Document 8: Griebel G., Soubrie P., 99, 6370a-6375, 2002.

Patent Document 1: WO01/55130 pamphlet

Patent Document 2: WO01/55134 pamphlet

Patent Document 3: WO01/64668 pamphlet

Patent Document 4: WO01/98295 pamphlet

Patent Document 5: WO03/008407 pamphlet

Patent Document 6: WO2004/009585 pamphlet

DISCLOSURE OF THE INVENTION

Problems to be Solved by the Present Invention

It is an object of the present invention to provide a drug that iseffective against pathology related to an arginine-vasopressin V1breceptor. More particularly, it is to provide a drug that is effectivein preventing or treating diseases such as depression, anxiety,Alzheimer's disease, Parkinson's disease, Huntington's disease, eatingdisorders, hypertension, gastrointestinal diseases, drug dependence,epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, headtrauma, inflammation, immunological diseases, and alopecia.

Means for Solving the Above Problems

As a result of diligent study, the inventors complete the presentinvention upon discovering a novel 1,3-dihydro-2H-indol-2-one derivativethat is selectively antagonistic toward an aruginine-vasopressin V1breceptor, has excellent metabolic stability, and exhibits goodintracerebral migration and high serum concentration.

Specifically, the present invention is a 1,3-dihydro-2H-indol-2-onederivative expressed by Formula 1:

(wherein R₁ is a halogen atom, a C₁ to C₄ alkyl group, a C₁ to C₄ alkoxygroup, a trifluoromethyl group, or a trifluoromethoxy group,

R₂ is a hydrogen atom, a halogen atom, a C₁ to C₄ alkyl group, a C₁ toC₄ alkoxy group, or a trifluoromethyl group, or R₂ is in the 6-positionof the indol-2-one and R₁ and R₂ join together to form a C₃ to C₆alkylene group,

R₃ is a halogen atom, a hydroxyl group, a C₁ to C₄ alkyl group, a C₁ toC₄ alkoxy group, or a trifluoromethoxy group,

R₄ is a hydrogen atom, a halogen atom, a C₁ to C₄ alkyl group, or a C₁to C₄ alkoxy group, or R₄ is in the 3-position of the phenyl and R₃ andR₄ join together to form a methylenedioxy group,

R₅ is a hydrogen atom or a fluorine atom,

R₆ is an ethylamino group, a dimethylamino group, an azetidin-1-ylgroup, or a C₁ to C₄ alkoxy group,

R₇ is a C₁ to C₄ alkoxy group, and

R₈ is a C₁ to C₄ alkoxy group),

or a pharmaceutically acceptable salt thereof.

A preferred compound of Formula 1 is a 1,3-dihydro-2H-indol-2-onederivative, or a pharmaceutically acceptable salt thereof, wherein

R₁ is a chlorine atom, a methyl group, a methoxy group, atrifluoromethyl group, or a trifluoromethoxy group,

R₂ is a hydrogen atom, a chlorine atom, a methyl group, or a methoxygroup,

R₃ is a fluorine atom or a methoxy group,

R₄ is a hydrogen atom, a chlorine atom, a methyl group, or a methoxygroup, or R₄ is in the 3-position of the phenyl and R₃ and R₄ jointogether to form a methylenedioxy group,

R₅ is a hydrogen atom or a fluorine atom,

R₆ is a dimethylamino group, an azetidin-1-yl group, or a methoxy group,

R₇ is a methoxy group and is in the 2-position of the phenyl, and

R₈ is a methoxy group.

Even more preferably, the compound of Formula 1 is a1,3-dihydro-2H-indol-2-one derivative or a pharmaceutically acceptablesalt thereof, expressed by the Formula 1a:

(wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are the same as defined inFormula 1), in which the substituent in the 2-position of thepyrrolidine has the (S) configuration.

The compound of Formula 1a is preferably in the form of a levorotatoryisomer.

Preferably, this compound is one of the compounds listed below:

-   (4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   (4S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4-difluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   methyl(4S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate    (diastereoisomer mixture);-   3-[(2S)-2-azetidin-1-ylcarbonyl)-4-fluoropyrrolidin-1-yl]-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one    (levorotatory isomer);-   (4R)-1-{3-(2,4-dimethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-5,6-dimethoxy-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   (4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   (4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   (4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   (4R)-1-[4,5-dichloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-5-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer);-   (4R)-1-{5-chloro-3-(5-chloro-2-methoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-4-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer); and-   (4R)-1-{3-(1,3-benzodioxol-4-yl)-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide    (levorotatory isomer).

Another aspect of the present invention is a method for manufacturing a1,3-dihydro-2H-indol-2-one derivative expressed by Formula 1 by reactinga compound expressed by

(wherein R₁, R₂, R₃, R₄, R₅, and R₆ are the same as defined inFormula 1) with a compound expressed by Formula 3:

(wherein R₇ and R₈ are the same as defined in Formula 1, and Hal is ahalogen atom) in the presence of a base.

Another aspect of the present invention is a compound expressed byFormula 2:

(wherein R₁, R₂, R₃, R₄, R₅, and R₆ are the same as defined in Formula1), or a salt thereof, which is useful as a synthetic intermediate ofthe compound expressed by Formula 1.

Another aspect of the present invention is a pharmaceutical compositioncontaining as an active ingredient the compound expressed by Formula 1or a pharmaceutically acceptable salt thereof. The meritorious effect ofthe present invention

The compound of the present invention is a selective vasopressin V1breceptor antagonist that has excellent metabolic stability and exhibitsgood intracerebral migration and high serum concentration, and is usefulin preventing or treating diseases such as depression, anxiety,Alzheimer's disease, Parkinson's disease, Huntington's disease, eatingdisorders, hypertension, gastrointestinal diseases, drug dependence,epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, headtrauma, inflammation, immunological diseases, and alopecia.

BEST MODE FOR CARRYING OUT THE INVENTION

The term “halogen atom” as used in the present invention means afluorine atom, chlorine atom, bromine atom, or iodine atom. A chlorineatom or fluorine atom is preferred.

The term “C₁ to C₄ alkyl group” means a linear or branched C₁ to C₄alkyl group, and specifically a methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, or tert-butyl group. Amethyl group is preferred.

The term “C₁ to C₄ alkoxy group” means a linear or branched C₁ to C₄alkoxy group, and specifically a methoxy group, ethoxy group, propoxygroup, isopropoxy group, butoxy group, isobutoxy group, or tert-butoxygroup. A methoxy group is preferred.

The term “C₃ to C₆ alkylene group” means a trimethylene group,tetramethylene group, pentamethylene group, or hexamethylene group. Atrimethylene group is preferred.

Pharmaceutically acceptable salts include, for example, salts ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andother such mineral acids, and salts of acetic acid, oxalic acid, lacticacid, tartaric acid, fumaric acid, maleic acid, succinic acid,trifluoroacetic acid, dichloroacetic acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenesulfonic acid, gluconic acid,benzenesulfonic acid, citric acid, and other such organic acids. Thecompound of the present invention can also be in the form of varioussolvates. Also, from the standpoint of applicability as a drug, ahydrate is sometimes preferable.

As long as it is a salt that can be used to synthesis the compoundexpressed by Formula 2, which is useful as an intermediate, there are noparticular restrictions on the salt of this compound, and may be amineral acid salt or an organic acid salt.

Mineral acid salts include, for example, hydrochlorides, hydrobromides,sulfates, phosphates, nitrates, hydrogensulfates, anddihydrogenphosphates.

Organic acid salts include, for example, acetates, oxalates, lactates,tartrates, fumarates, maleates, succinates, trifluoroacetates,dichloroacetates, methanesulfonates, p-toluenesulfonates,naphthalenesulfonates, gluconates, benzenesulfonates, and citrates.

The compound of the present invention also includes compounds in whichone or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms,or sulfur atoms have been substituted with a radioactive isotope or astable isotope. These labeled compounds are useful in metabolic orpharmacokinetic research, or in biochemical analysis as receptorligands.

The compound of the present invention can be pharmaceutically formulatedby being combined with one or more pharmaceutically acceptable carriers,excipients, or diluents. Examples of such carriers, excipients, anddiluents include water, lactose, dextrose, fructose, sucrose, sorbitol,mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin,alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup,methyl cellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate,talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil,soy oil, and various other oils.

Also, the above carriers, excipients, and diluents can be mixed asneeded with commonly used thickeners, binders, disintegrants, pHregulators, solvents, and other such additives, and can be prepared astablets, pills, capsules, granules, a powder, a liquid, a lotion, asuspension, an ointment, an injection, a skin patch, or other oral orparenteral drug by a standard formulation technique. The compound of thepresent invention can be administered orally or parenterally to apatient one or more times per day in a dose of 0.001 to 500 mg. Thisdose can be suitably increased or decreased according to the type ofdisease to be treated, or the age, weight, symptoms, and so forth of thepatient.

The compound of the present invention can be manufactured by thefollowing method, for example.

The compound of the present invention can be manufactured by reacting acompound expressed by Formula 2:

(wherein R₁, R₂, R₃, R₄, R₅, and R₆ are the same as defined inFormula 1) with a compound expressed by Formula 3:

(wherein R₇ and R₈ are the same as defined in Formula 1, and Hal is ahalogen atom) in the presence of a base. If necessary, the compound thusobtained can be converted into a pharmaceutically acceptable salt.

The reaction is conducted under the following conditions, for example:in the presence of a metal hydride such as sodium hydride or an alkalimetal alkoxide such as potassium tert-butoxide, in a nonaqueous solventsuch as N,N-dimethylformamide or tetrahydrofuran, or in a mixture ofthese solvents, and at a temperature from −70° C. to +60° C.

The compound of the present invention can be obtained by taking thereaction product out of the reaction mixture and purified it by astandard method, such as crystallization or chromatography.

The compound of the present invention can be obtained in a free form orisolated as a salt by a standard method. When the compound of thepresent invention is obtained in a free form, salt formation can beperformed by treatment with an acid in an organic solvent. For instance,a free form can be dissolved along with an acid in diethyl ether oranother ether, isopropyl alcohol or another alcohol, acetone,dichloromethane, ethyl acetate, acetonitrile, or the like, and theabove-mentioned salt obtained by a standard method.

The acids that can be used include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, oxalicacid, lactic acid, tartaric acid, fumaric acid, maleic acid, succinicacid, trifluoroacetic acid, dichloroacetic acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid,gluconic acid, and citric acid.

At the end of this reaction, the compound of the present invention issometimes isolated as a hydrochloride, oxalate, or the like, forexample, but if necessary, a free form can be obtained by neutralizingthe obtained salt with an alkali metal hydrogencarbonate or alkali metalcarbonate such as sodium hydrogencarbonate or sodium carbonate, ortriethylamine or sodium hydroxide.

The compound expressed by Formula 2 can be manufactured by reacting a3-halo-1,3-dihydro-2H-indol-2-one derivative expressed by Formula 5:

(wherein R₁, R₂, R₃, and R₄ are the same as defined in Formula 1, andHal is a halogen atom) with a compound expressed by Formula 4:

(wherein R₅ and R₆ are the same as defined in Formula 1), or a salt ofthis compound, in the presence of a base, such as diisopropylethylamineor triethylamine, in an inert solvent, such as dichloromethane ortetrahydrofuran, or in a mixture of these solvents, and at a temperaturebetween room temperature and close to the boiling point of the solvent.

The compound expressed by Formula 3 is a known compound disclosed inEP0469984, WO95/18105, and elsewhere, and can be manufactured by themethods described in these publications. For instance, the compoundexpressed by Formula 3 can be manufactured by halogenating abenzenesulfonic acid derivative or a salt thereof, such as a sodium orpotassium salt.

The reaction proceeds in the presence of a halogenating agent, such asthionyl chloride or phosphorus oxychloride, in a non-solvent or an inertsolvent, such as a halogenated hydrocarbon, N,N-dimethylformamide, oranother such solvent, and at a temperature from −10° C. to 200° C.

2,4-dimethoxybenzenesulfonyl chloride is commercially available, or canbe manufactured according to the methods described in a publication(Journal of American Chemical Society, 1952, 74, 2006).

The compound expressed by Formula 5 can be manufactured, for example, bythe methods described in WO95/18105, WO01/74775, WO01/55130, WO01/55134,WO01/64668, WO01/98295, WO03/008407, and elsewhere.

For example, a compound expressed by Formula 6a:

(wherein R₁, R₂, R₃, and R₄ are the same as defined in Formula 1) can beconverted into a compound expressed by Formula 5 (Hal=Cl) by causingthionyl chloride to act on the compound in the presence of a base suchas pyridine, in an inert solvent such as dichloromethane, and at atemperature between 0° C. and room temperature.

In another method for manufacturing a compound expressed by Formula 5, acompound expressed by Formula 6b:

(wherein R₁, R₂, R₃, and R₄ are the same as defined in Formula 1) can beconverted by using a halogenating agent such as bromine orN-chlorosuccinimide according to the method described in a publication(Farm. Zh. (K-iev), 1976, 5, 30-33).

The compound expressed by Formula 6a can be manufactured, for example,by the methods described in WO95/18105, WO01/74775, WO01/55130,WO01/55134, WO01/64668, WO01/98295, WO03/008407, and elsewhere.

The compound expressed by Formula 4 generally can be manufactured by thesynthesis route shown in Scheme 1. Pr is a protective group for anitrogen atom, and in particular is a benzyloxycarbonyl group ortert-butoxycarbonyl group.

In step 1-1a of Scheme 1, a compound 8 can be manufactured byintroducing a protective group according to a standard method to anitrogen atom of compound 7: (4R)- or (4S)-4-hydroxy-L-proline or (4R)-or (4S)-4-hydroxy-D-proline. In the subsequent step 1-2a, a compound 10can be manufactured by the esterification or amidation of compound 8according to a standard method. Similarly, a compound 9 can bemanufactured by the esterification or amidation of the carboxylic acidof compound 7 in step 1-1b according to a standard method, and compound10 can then be manufactured by introducing a protective group (step1-2b) according to a standard method to a nitrogen atom of the obtainedcompound 9.

The amidation reaction is generally as follows. A method involving theuse of a dehydrating condensation agent is an example. Examples ofdehydrating condensation agents include1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,dicyclohexylcarbodiimide, diphenylphosphonylazide, andcarbonyldiimidazole. If necessary, an activator such as1-hydroxybenzotriazole or hydroxysuccinimide can be used. Examples ofthe reaction solvent include dichloromethane, chloroform,1,2-dichloroethane, N,N-dimethylformamide, tetrahydrofuran, dioxane,toluene, ethyl acetate, and mixtures of these solvents. A base can beused here, and examples of the base include triethylamine,diisopropylethylamine, and other such organic amines, sodium2-ethylhexanoate, potassium 2-ethylhexanoate, and other such organicacid salts, and potassium carbonate and other such inorganic bases. Thereaction can be conducted between −50° C. and close to the boiling pointof the reaction solvent.

Also, amidation can be performed using a mixed acid anhydride obtainedfrom a carboxylic acid and a chlorocarbonic ester, for example. Examplesof the solvent used in these reactions include tetrahydrofuran, dioxane,dichloromethane, chloroform, N,N-dimethylformamide, toluene, ethylacetate, and other solvents that do not participate in the reaction, ora mixture of these solvents. A base can be used here, and examples ofthe base include triethylamine, diisopropylethylamine, and other suchorganic amines, sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, andother such organic acid salts, and potassium carbonate and other suchinorganic bases. The reaction can be conducted between −50° C. and closeto the boiling point of the reaction solvent.

Common esterification reactions of a carboxylic acid include thefollowing. For example, methyl esterification can be performed by usingdiazomethane or another such diazo compound. The solvent used here canbe dichloromethane, chloroform, methanol, ethanol, or another suchsolvent, or a mixture of these solvents. Further, esterification can beperformed by converting a carboxylic acid into an acid halide, andcausing an alcohol compound to act on this product. An acid halide canbe produced by using thionyl chloride, thionyl bromide, phosphorusoxychloride, or the like. Examples of the solvent used here includedichloromethane, chloroform, N,N-dimethylformamide, toluene,tetrahydrofuran, and other solvents that do not participate in thereaction, or a mixture of these solvents. Esterification can beperformed by subjecting the acid halide thus prepared to the action ofan alcohol such as methanol or ethanol. This reaction is brought aboutby adding an alcohol to the acid halogenation reaction system, or mayinvolve subjecting an isolated acid halide to the action of an alcohol.

Another possible method is one involving the use of a dehydratingcondensation agent. Examples of dehydrating condensation agents include1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,dicyclohexylcarbodiimide, diphenylphosphonylazide, andcarbonyldiimidazole. Examples of the reaction solvent includedichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide,tetrahydrofuran, dioxane, toluene, ethyl acetate, and mixtures of thesesolvents. A base can be used here, and examples of the base includetriethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine, andother such amines, sodium 2-ethylhexanoate, potassium 2-ethylhexanoate,and other such organic acid salts, and potassium carbonate and othersuch inorganic bases. The reaction can be conducted between −50° C. andclose to the boiling point of the reaction solvent.

Also, esterification can be performed using a mixed acid anhydrideobtained from a carboxylic acid and a chlorocarbonic ester, ordi-tert-butyl dicarbonate, for example. Examples of the solvent used inthese reactions include tetrahydrofuran, dioxane, dichloromethane,chloroform, N,N-dimethylformamide, toluene, ethyl acetate, and othersolvents that do not participate in the reaction, or a mixture of thesesolvents. A base can be used here, and examples of the base includetriethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine, andother such organic amines, sodium 2-ethylhexanoate, potassium2-ethylhexanoate, and other such organic acid salts, and potassiumcarbonate and other such inorganic bases. The reaction can be conductedbetween −50° C. and close to the boiling point of the reaction solvent.

At some point in the process of preparing the compound defined byFormula 4, or an intermediate thereof, it will probably be necessary ordesirable to protect reactive or sensitive functional groups, such asamines and carboxylic acids, present in any of the molecules concerned.This protection can be accomplished using conventional protectinggroups, such as those described in Protective Groups in OrganicChemistry, by J. F. W. McOmie, published in 1973 by Plenum Press, or inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. M.Wuts, published in 1991 by John Wiley & Sons. The protecting groups alsobe removed by the methods outlined in the above two booklets.

The protection of amino groups can be carried out, for example, usingdi-tert-butyl dicarbonate, benzyl chloroformate, or the like, and in thepresence of a suitable base. Examples of the base include triethylamine,diisopropylethylamine, and other such amines, and potassium carbonateand other such inorganic bases. Examples of the solvent used in thesereactions include tetrahydrofuran, dioxane, dichloromethane, chloroform,N,N-dimethylformamide, toluene, ethyl acetate, water, and other solventsthat do not participate in the reaction, or a mixture of these solvents.The reaction can be conducted between −50° C. and +50° C.

Protection of carboxylic acids is generally accomplished byesterification. This esterification is performed according to the methoddescribed above.

In the fluorination of a pyrrolidine ring, a 4-fluoro form can beobtained from a 4-hydroxy form, and a 4,4-difluoro form can be obtainedfrom a 4-keto form, for example.

In scheme 1, an example of the monofluorination in step 1-3a is a methodinvolving the use of diethylaminosulfur trifluoride or dimethylsulfurtrifluoride, a mixture of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propaneand 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene, or the like. Theuse of a mixture of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene will give good resultswhen cesium fluoride, sodium fluoride, or potassium fluoride is admixedin the reaction system. Examples of the solvent used in these reactionsinclude tetrahydrofuran, dioxane, dichloromethane, chloroform,1,2-dichloroethane, toluene, and other solvents that do not participatein the reaction, or a mixture of these solvents. The reaction iscommenced between −78° C. and room temperature, and is then continuedbetween room temperature and 50° C. An example of monofluorination is amethod in which a hydroxyl group is converted into a leaving group, andthen converted into a fluoro group. Examples of the conversion of aleaving group include chlorination, bromination, iodation,methanesulfonylation, and p-toluenesulfonylation.

(wherein R₆ is the same as defined in Formula 1, and Pr is the same asabove.)

Examples of a chlorination reaction include the use of carbontetrachloride and triphenylphosphine, the use of thionyl chloride orphosphorus oxychloride, and a method in which a leaving group isproduced using tosyl chloride or the like, and then conversion isperformed with lithium chloride or the like. Examples of the solventused in these reactions include tetrahydrofuran, dioxane,dichloromethane, chloroform, N,N-dimethylformamide, and other solventsthat do not participate in the reaction, or a mixture of these solvents.These reactions can be carried out between −50° C. and 100° C. Anexample of a bromination reaction is the use of carbon tetrachloride andtriphenylphosphine. This reaction can be conducted in tetrahydrofuran,dioxane, dichloromethane, chloroform, N,N-dimethylformamide, and othersolvents that do not participate in the reaction, or a mixture of thesesolvents, between −50° C. and 50° C. An example of an iodation reactionis the use of iodine, triphenylphosphine, and imidazole. This reactioncan be conducted in tetrahydrofuran, dioxane, dichloromethane,chloroform, N,N-dimethylformamide, and other solvents that do notparticipate in the reaction, or a mixture of these solvents. Thesereactions are conducted at a temperature between −50° C. and 100° C.

Methanesulfonylation and p-toluenesulfonylation can be performed usingmethanesulfonyl chloride and p-toluenesulfonyl chloride, respectively,for example. A suitable base may be added here. Examples of bases thatcan be added include triethylamine, diisopropylethylamine, and othersuch organic amines, and potassium carbonate and other such inorganicbases. The reaction solvent here can be N,N-dimethylformamide,tetrahydrofuran, dioxane, dichloromethane, chloroform,1,2-dichloroethane, and other solvents that do not participate in thereaction, or a mixture of these solvents, and the reaction can beconducted at a temperature between −50° C. and 50° C.

Examples of a method involving conversion into a leaving group and thenconversion into a fluoro group include a method involving the reactionof tetrabutylammonium fluoride, cesium fluoride, potassium fluoride,sodium fluoride, or the like. These reactions can be conducted intetrahydrofuran, dioxane, dichloromethane, chloroform,N,N-dimethylformamide, water, and other solvents that do not participatein the reaction, or a mixture of these solvents, and at a temperaturebetween −50 and 100° C.

Difluorination is performed after a hydroxyl group has been oxidizedinto a ketone group.

This oxidation (step 1-3b) can be accomplished, for example, usingpyridinium chlorochromate, pyridinium dichromate, or other chromic acid.Examples of the reaction solvent include dichloromethane and chloroform,and the reaction can be conducted at a temperature between 0° C. andclose to the boiling point of the reaction solvent.

The reaction can also involve the use of a Dess-Martin reagent(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one). Examples ofthe reaction solvent include dichloromethane and chloroform, and thereaction can be conducted at a temperature between 0° C. and 40° C.

As another example, the reaction can involve the use of IBX(1-hydroxy-1,2-benziodoxol-3-(1H)-one 1-oxide). Dimethyl sulfoxide canbe used as the reaction solvent, and the reaction solution can befurther diluted with a solvent that does not participate in thereaction, such as tetrahydrofuran, dichloromethane, or chloroform. Thereaction temperature can be from 0° C. to 40° C.

Other than the above, there are no particular restrictions on thisoxidation reaction, as long as it is a method that allows an alcohol tobe oxidized into a ketone. Examples include a reaction involvingdimethyl sulfoxide and an activator (such as oxalyl chloride,N-chlorosuccinimide, or dicyclohexylcarbodiimide), or an oxidationmethod involving the use of tetra-n-propylammonium perruthenate(VII) andN-methylmorpholine oxide. A comprehensive overview of this oxidationreaction can be found in Comprehensive Organic Transformation, byRichard C. Larock, Wiley-VHC, 1999, 604.

Also, in Scheme 1, examples of the difluorination in step 1-4b includethe use of dimethylsulfur trifluoride, [bis(2-methoxyethyl)amino]sulfurtrifluoride, or another such fluorination agent. These reactions can beconducted in tetrahydrofuran, dioxane, dichloromethane, chloroform,1,2-dichloroethane, toluene and mixtures of these solvents. The reactionis commenced between −78° C. and room temperature, and is then continuedbetween room temperature and close to the boiling point of the solvent.

A compound 14 or 15, or a salt thereof, can be manufactured by removingthe protective group from the nitrogen atom by a standard method (steps1-4a and 1-5b).

For example, when the protection is achieved with a group that isremoved with a tert-butyloxycarbonyl group or another such acid, theprotective group can be removed using hydrochloric acid, sulfuric acid,trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, oranother such acid. The deprotection here can be performed by diluting ordissolving the acid with an organic solvent, and the reaction can beconducted at temperature between −50° C. and 50° C. Examples of theorganic solvent include ethanol, methanol, tetrahydrofuran,N,N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane,and mixtures of these solvents.

Further, when the protection is achieved with a group that is removed byhydrogenolysis of a benzyloxycarbonyl group, for example, the protectivegroup can be removed by a hydrogenolysis reaction using a metal catalystsuch as palladium. The solvent can be ethanol, methanol,tetrahydrofuran, ethyl acetate, and other such solvents that do notparticipate in the reaction, and mixtures of these solvents. Thereaction can be conducted between 0° C. and 100° C. Hydrogen gas canalso be used for this reaction, and a formic acid/ammonium formatecombination can also be used.

Further, when the protection is achieved with a group that is removedwith a group such as a fluorenyloxycarbonyl group that is removed with abase, deprotection can be accomplished using a base such asdiethylamine, piperidine, ammonia, sodium hydroxide, or potassiumhydroxide. These bases can be used alone, or after being diluted,dissolved, or suspended with a solvent. Solvents that can be used hereinclude water, ethanol, methanol, tetrahydrofuran,N,N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane,and so forth, as well as mixtures of these solvents. The reaction can beconducted at a temperature between 0° C. and close to the boiling pointof the solvent.

Further, when the protection is achieved with a group that is removedwith a metal catalyst such as allyloxycarbonyl, deprotection can beaccomplished by using tetrakis(triphenylphosphine)palladium or the likeas a catalyst or reagent. The reaction here can be conducted indichloromethane, chloroform, tetrahydrofuran, or another such solventthat will not participate in the reaction, and at a temperature between0° C. and close to the boiling point of the solvent.

(4R)- or (4S)-4-hydroxy-L-proline or (4R)- or (4S)-4-hydroxy-D-prolinecan be purchased commercially.

Of the compounds defined by Formula 4,(4R)-4-fluoro-N,N-dimethyl-L-prolinamide (21) can be manufactured by thesynthesis route shown in Scheme 2.

Compound 16 or 18, that is, (4R)-N-protected-4-hydroxy-L-proline (16) or(4S)-N-protected-4-hydroxy-L-proline (18), is used as the synthesis rawmaterial, N,N-dimethylamidation is performed according to a standardmethod for forming amide bonds in step 2-1a and 2-1b, and thenfluorination is performed in steps 2-2a and 2-2b using a fluorinationagent, and particularly a mixture of1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene. In this fluorination,good results will be obtained when sodium fluoride, potassium fluoride,or cesium fluoride is present in the reaction system. The reaction isconducted in tetrahydrofuran, dioxane, dichloromethane, chloroform,1,2-dichloroethane, toluene, or another solvent that will notparticipate in the reaction, or in a mixture of these solvents, and iscommenced between −78° C. and room temperature, and then continuedbetween room temperature and close to the boiling point of the solvent.

In this case, the steric configuration of the 4-position of compounds 16and 18, which are the synthesis raw materials, may be either the (R)configuration or the (S) configuration, and a 4-fluoride compound 20 of(4R) configuration can be obtained in either case. The compound 20 thusobtained is deprotected by a standard method to obtain a compound 21 ora salt thereof.

Of the compounds expressed by Formula 4, when R₅ is a hydrogen atom andR₆ is an alkoxy group, a dimethylamino group, or an ethylamino group,the compound can be manufactured by the synthesis route shown in Scheme3. The methyl orethyl(2S,4R)-N-protected-4-hydroxy-2-pyrrolidinecarboxylate expressed bycompound 22 is used as the synthesis raw material, and fluorine of (4S)configuration is introduced by standard fluorination (step 3-1) of ahydroxyl group. The compound 23 thus obtained can be deprotected by astandard method (step 3-5) to obtain a methyl orethyl(4R)-4-fluoro-L-prolinate form 27 or a salt thereof. Meanwhile,compound 23 can have its ester hydrolyzed (step 3-2) by a standardmethod to manufacture a carboxylic acid form 24. The carboxylic acidform 24 thus obtained can be amidated (step 3-3) according to a standardmethod for forming peptide bonds, and then the protective group of thenitrogen atom can be removed by a standard method (step 3-4) tomanufacture a (4S)-4-fluoro-N,N-dimethyl or —N-ethyl-L-prolinamide form26 or a salt thereof.

The hydrolysis of the ester can be accomplished, for example, by using abase such as potassium carbonate or another metal carbonate, or sodiumhydroxide or another metal hydroxide. The reaction solvent here can bemethanol, ethanol, or another alcohol, tetrahydrofuran, dioxane,N,N-dimethylformamide, water, or the like, or a mixture of thesesolvents. The reaction can be conducted at a temperature between −20° C.and close to the boiling point of the reaction solvent.

When the protection is achieved with a group that is removed with theacid of another ester, such as a tert-butyl ester, the protective groupcan be removed using hydrochloric acid, sulfuric acid, trifluoroaceticacid, p-toluenesulfonic acid, methanesulfonic acid, or another suchacid. The deprotection here can be performed by diluting or dissolvingthe acid with an organic solvent or water, and the reaction can beconducted at temperature between −50° C. and +50° C. Examples of theorganic solvent include ethanol, methanol, tetrahydrofuran,N,N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane,and mixtures of these solvents.

Further, when the protection is achieved with a group that is removed byhydrogenolysis of a benzyl ester or the like, the protective group canbe removed by a hydrogenolysis reaction using a metal catalyst such aspalladium. The solvent can be ethanol, methanol, tetrahydrofuran, ethylacetate, and other such solvents that do not participate in thereaction, and mixtures of these solvents. The reaction can be conductedbetween 0° C. and 100° C. Hydrogen gas can also be used for thisreaction, and a formic acid/ammonium formate combination can also beused.

Further, when the protection is achieved with a group that is removedwith a metal catalyst such as an allyl ester, deprotection can beaccomplished by using tetrakis(triphenylphosphine)palladium or the likeas a catalyst or reagent. The reaction here can be conducted indichloromethane, chloroform, tetrahydrofuran, or another such solventthat will not participate in the reaction, and at a temperature between0° C. and close to the boiling point of the solvent.

Of the compounds expressed by Formula 4, when R₅ is a fluorine atom andR₆ is an dimethylamino group or an ethylamino group, the compound can bemanufactured by the synthesis route shown in Scheme 4.4,4-difluoro-N-protected-2-pyrrolidine carboxylate, which is one of theabove-mentioned compounds 13 in Scheme 1, can be used as the synthesisraw material, and a carboxylic acid form 28 can be obtained byhydrolysis in step 4-1. The carboxylic acid form 28 thus obtained issubjected to amide bond formation by a standard method to obtaincompound 29 (step 4-2). The protective group of the nitrogen atom isremoved by a standard method (step 4-3) to obtain compound 30 or a saltthereof.

The present invention will now be described in more specific terms bygiving examples and test examples. In these examples, “silica gel 60”and “silica gel 60N” refer to silica gels marketed by Kanto Chemical.“Chromatorex NH” refers to a silica gel marketed by Fuji Silysia. Theprogress of the reaction was tracked by thin layer chromatography (TLC)using a 0.25 mm silica gel 60F₂₅₄ plate (made by Merck). The coloring ofthe TLC plate was observed using UV (254 nm) or a 20% sodiumphosphomolybdate/ethanol solution.

The ¹H-NMR spectrum uses tetramethylsilane as an internal reference, andthe chemical shift was given in ppm.

EXAMPLE 1 Synthesis of(4R)-1-[5-chloro-1-[2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 1-1a: Synthesis oftert-butyl(2S,4R)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate

24.9 g of 1-hydroxybenzotriazole monohydrate and 24.9 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedunder ice cooling to a 250 mL tetrahydrofuran solution of 25.1 g of(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and stirred for 15minutes. 10.7 g of a 50% dimethylamine aqueous solution was addeddropwise over a period of 10 minutes to the reaction mixture, and thereaction mixture was stirred for 15 hours at room temperature. Thesolvent was distilled off under reduced pressure, after which 100 mL ofa saturated sodium hydrogencarbonate aqueous solution was added andextraction was performed with chloroform (50 mL×2). The extract wasdried with anhydrous sodium sulfate, the drying agent was filtered off,and the reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel 60N, mobilephase: chloroform/methanol=20/1 to 9/1; v/v) to obtain 26.2 g of thetitled compound (colorless solid).

MS (ESI pos.) m/z: 281([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.40 &1.45 (each-s, 9H), 1.95-2.36 (m, 3H), 2.97 & 2.98 (each-s, 3H), 3.08 &3.13 (each-s, 3H), 3.41-3.62 (m, 1H), 3.63-3.76 (m, 1H), 4.46-4.60 (m,1H), 4.69-4.87 (m, 1H)

Step 1-2a: Synthesis oftert-butyl(2S,4R)-2-[(dimethylamino)carbonyl]-4-fluoropyrrolidine-1-carboxylate

26.6 g of a mixture (approximately 3:1) of1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise overa period of 10 minutes under ice cooling to a suspension of 25.7 g ofthe compound obtained in step 1-1a and 5.00 g of sodium fluoride in 260mL of dichloromethane, after which the reaction mixture was stirred for16 hours at room temperature. 100 mL of a 5% potassium carbonate aqueoussolution was added under ice cooling to the reaction solution, and thereaction mixture was stirred for 30 minutes at the same temperature.After liquid separation, the aqueous layer thus obtained was extractedwith chloroform, and the combined organic layer was washed with 50 mL ofsaturated brine and dried with magnesium sulfate, after which the dryingagent was filtered off and the solvent was distilled off under reducedpressure. The residue thus obtained was subjected to columnchromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1to 10/0; v/v) to obtain 12.2 g of the titled compound (pale yellowsolid).

MS (ESI pos.) m/z: 283([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.42 &1.46 (each-s, 9H), 2.00-2.26 (m, 1H), 2.36-2.55 (m, 1H), 2.98 & 2.99(each-s, 3H), 3.10 & 3.16 (each-s, 3H), 3.58-3.99 (m, 2H), 4.71-4.92 (m,1H), 5.12-5.38 (m, 1H)

Step 1-1b: Synthesis oftert-butyl(2S,4S)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate

9.95 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloridewas added under ice cooling to a 100 mL tetrahydrofuran solution of 10.0g of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and 8.77 g of1-hydroxybenzotriazole monohydrate, and the reaction mixture was stirredfor 30 minutes at the same temperature. 15.6 g of a 50% dimethylamineaqueous solution was than added to the reaction solution, after whichthe reaction mixture was stirred for 1 hour at room temperature. 100 mLof chloroform and 50 mL of a 5% potassium carbonate aqueous solutionwere added to the reaction solution, liquid separation was performed,the aqueous layer was extracted with chloroform (30 mL×2), and thecombined organic layer was washed with 30 mL of saturated brine anddried with magnesium sulfate, after which the drying agent was filteredoff and the solvent was distilled off under reduced pressure. Theresidue thus obtained was subjected to column chromatography (silica gel60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain8.66 g of the titled compound (colorless solid).

MS (ESI pos.) m/z: 281([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.42 &1.45 (each-s, 9H), 1.91-1.99 (m, 1H), 2.17-2.35 (m, 1H), 3.02 & 3.03(each-s, 3H), 3.16 & 3.27 (each-s, 3H), 3.48-3.56 (m, 1H), 3.64-3.86 (m,1H), 4.26-4.37 (m, 1H), 4.66-4.84 (m, 1H), 5.28-5.83 (m, 1H)

Step 1-2b: Synthesis oftert-butyl(2S,4R)-2-[(dimethylamino)carbonyl]-4-fluoropyrrolidine-1-carboxylate

8.85 g of a mixture (approximately 3:1) of1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise overa period of 2 minutes under ice cooling to a suspension of 8.54 g of thecompound obtained in step 1-1b and 1.67 g of sodium fluoride in 90 mL ofdichloromethane, after which the reaction mixture was stirred for 15hours at room temperature. 200 mL of a saturated sodiumhydrogencarbonate aqueous solution was added dropwise to the reactionsolution over a period of 3 minutes, and the reaction mixture wasstirred for 1 hour. After liquid separation, the aqueous layer wasextracted with chloroform (30 mL×2), and the combined organic layer waswashed with 50 mL of saturated brine and dried with magnesium sulfate,after which the drying agent was filtered off and the reaction mixturewas concentrated under reduced pressure. The residue thus obtained wassubjected to column chromatography (silica gel 60, mobile phase: ethylacetate/n-hexane=1/1 to 10/0; v/v) to obtain 7.54 g of the titledcompound (pale yellow solid).

Step 1-3: Synthesis of (4R)-4-fluoro-N,N-dimethyl-L-prolinamidetrifluoroacetate

10.5 mL of trifluoroacetic acid was added under ice cooling to a 25 mLchloroform solution of 3.50 g of the compound obtained in step 1-2b,after which the reaction mixture was stirred for 3 hours at roomtemperature. The solvent was then distilled off under reduced pressure,which gave 7.27 g of residue (yellow oily substance). This compound wasused in the following reaction without being purified.

MS (ESI pos.) m/z: 161 ([M+H]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm);1.97-2.21 (m, 1H), 2.68-2.87 (m, 1H), 2.92 (s, 3H), 3.02 (s, 3H),3.37-3.62 (m, 2H), 4.72-4.85 (m, 1H), 5.36-5.60 (m, 1H), 8.83 (brs, 1H),9.99 (brs, 1H)

Step 1-4: Synthesis of(4R)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide

7.47 g of triethylamine was added under ice cooling to a suspension of3.78 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-oneand the compound (unpurified) obtained in step 1-3 in 40 mL ofchloroform under a nitrogen atmosphere, after which the reaction mixturewas stirred for 13 hours at room temperature. 40 mL of a 5% potassiumcarbonate aqueous solution was poured into the reaction solution understirring, and extraction was performed with chloroform (30 mL×2). Thecombined organic layer was washed with 50 mL of saturated brine anddried with magnesium sulfate, then the drying agent was filtered off andthe solvent was distilled off under reduced pressure to obtain 6.43 g ofa brown solid. This was separated and purified by column chromatography(silica gel 60, mobile phase: ethyl acetate/aceton=4/1; v/v) to obtaintwo kinds of diastereoisomer of the titled compound in amounts of 2.06 g(isomer A: colorless powder) and 2.74 g (isomer B: colorless powder).

Isomer A: [α]_(D) ²⁹=+129° (c=0.578, chloroform) MS (ESI pos.) m/z:454([M+Na]⁺), (ESI neg.) m/z: 430([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.65-1.94 (m, 1H), 2.17-2.35 (m, 1H), 2.42-2.85 (m, 6H),3.22-3.56 (m, 1H), 3.47 (s, 3H), 3.75-3.97 (m, 2H), 5.05-5.31 (m, 1H),6.50 (s, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 7.07-7.21(m, 2H), 7.29 (t, J=7.5 Hz, 1H), 8.05 (d, J=7.5 Hz, 1H), 10.52 (s, 1H)

Isomer B: [α]_(D) ²⁸=−188° (c=0.219, chloroform) MS (ESI pos.) m/z:454([M+Na]⁺), (ESI neg.) m/z: 430([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.79-1.99 (m, 1H), 2.23-2.54 (m, 7H), 2.88-3.06 (m, 1H),3.42-3.72 (m, 1H), 3.46 (s, 3H), 4.58-4.70 (m, 1H), 5.18-5.43 (m, 1H),6.74 (d, J=8.2 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.91 (dd, J=8.2, 1.09Hz, 1H), 6.97-7.05 (m, 1H), 7.15-7.20 (m, 1H), 7.23-7.31 (m, 1H), 7.86(dd, J=7.7, 1.5 Hz, 1H), 10.33 (s, 1H)

Step 1-5: Synthesis of(4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

2.00 g of isomer B obtained in step 1-4 was added under ice cooling to a20 mL dimethylformamide solution of 0.215 g of sodium hydride under anitrogen atmosphere, and the reaction mixture was stirred for 40minutes. 5 mL dimethylformamide solution of 1.27 g of2,4-dimethoxybenzenesulfonyl chloride was added dropwise to the reactionmixture. The reaction mixture was stirred for 35 minutes at the sametemperature, after which 50 mL of chloroform and 50 mL of a 5% potassiumcarbonate aqueous solution were added, and the reaction mixture wasstirred for another 1 hour at room temperature. After liquid separation,the aqueous layer was extracted with chloroform (15 mL×2), and thecombined organic layer was dried with magnesium sulfate, after which thedrying agent was filtered off and the solvent was distilled off underreduced pressure to obtain 3.74 g of residue (amorphous, pale yellow).The residue thus obtained was subjected to column chromatography (silicagel 60, mobile phase: ethyl acetate/n-hexane=1/1; v/v) to obtain 2.30 gof the titled compound (amorphous, colorless amorphous).

[α]_(D) ²⁸=−199° (c=0.590, chloroform) MS (ESI pos.) m/z: 654([M+Na]⁺)¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.87-3.94 (m, 4H), 2.33 (s, 3H), 2.76(s, 3H), 3.56-3.79 (m, 6H), 3.86 (s, 3H), 4.76-5.00 (m, 1H), 5.15-5.43(m, 1H), 6.43 (d, J=2.2 Hz, 1H), 6.58-6.64 (m, 1H), 6.78 (d, J=8.4 Hz,1H), 6.92-7.00 (m, 1H), 7.07 (brs, 1H), 7.20-7.31 (m, 2H), 7.72-7.81 (m,1H), 7.92 (d, J=8.7 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H)

EXAMPLE 2 Synthesis of(4S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 2-1: Synthesis of1-tert-butyl-2-methyl(2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate

32.8 g of a mixture (approximately 3:1) of1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise overa period of 10 minutes under ice cooling to a suspension of 30.0 g ofthe 1-tert-butyl-2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylateand 6.16 g of sodium fluoride in 180 mL of dichloromethane, after whichthe reaction mixture was stirred for 15 hours at room temperature. Thereaction solution was poured into 200 mL of a saturated sodiumhydrogencarbonate aqueous solution under stirring and ice cooling, andthe reaction mixture was stirred for 15 minutes. After the reactionmixture was allowed to stand and undergo liquid separation, the organiclayer thus obtained distilled under reduced pressure to remove thesolvent and obtain a residue. The aqueous layer was extracted with 60 mLof ethyl acetate and combined with the above-mentioned residue. Theorganic layer was washed with 40 mL of 10% potassium hydrogensulfateaqueous solution and saturated brine and dried with magnesium sulfate,after which the drying agent was filtered off and the solvent wasdistilled off under reduced pressure. The residue thus obtained wasdistilled under reduced pressure (b.p. 81 to 83° C./11 hPa) to removethe unnecessary components and obtain 36.8 g of residue (yellow oilysubstance). The residue thus obtained was subjected to columnchromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1;v/v) to obtain 34.6 g of the titled compound (colorless oily substance).

MS (ESI pos.) m/z: 270([M+Na]⁺) ¹H-NMR (200 MHz, DMSO-d₆) δ (ppm); 1.35& 1.41 (each-s, 9H), 2.13-2.76 (m, 2H), 3.19-3.74 (m, 5H), 4.33-4.45 (m,1H), 5.13-5.39 (m, 1H)

Step 2-2: Synthesis of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline

A 181 mL methanol solution of 30.2 g of the compound obtained in step2-1 was added dropwise over a period of 60 minutes under stirring to 86mL of a 2 mol/L sodium hydroxide aqueous solution, after which thereaction mixture was stirred for 16 hours at room temperature. Themethanol was distilled off under reduced pressure, 136 mL of toluene wasadded and stirred, and then the aqueous layer was separated and stirredunder ice cooling. 122 mL of 2 mol/L hydrochloric acid was addeddropwise over a period of 40 minutes, after which extraction wasperformed with ethyl acetate (230 mL×2), the combined organic layer waswashed with 128 mL of saturated brine and dried with sodium sulfate,then the drying agent was filtered off and the solvent was distilled offunder reduced pressure to obtain 25.1 g of a colorless solid. 91 mL ofdiisopropyl ether was added and stirred for 2 hours at room temperature,after which the crystals were filtered off to obtain 20.2 g of thetitled compound (colorless solid). The filtrate was concentrated underreduced pressure, and 9 mL of diisopropyl ether was added and stirredfor 2 hours at room temperature, after which the crystals were filteredoff to obtain 0.54 g of the titled compound (colorless solid).

MS (ESI neg.) m/z: 232([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.36 &1.41 (each-s, 9H) 2.13-2.63 (m, 2H), 3.29-3.71 (m, 2H), 4.28 (t, J=9.1Hz, 1H), 5.13-5.39 (m, 1H) 12.55 (brs, 1H)

Step 2-3: Synthesis oftert-butyl(2S,4S)-2-[(dimethylamino)carbonyl]-4-fluoropyrrolidine-1-carboxylate

19.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloridewas added under ice cooling to a 200 mL tetrahydrofuran solution of 19.9g of the compound obtained in step 2-2 and 17.3 g of1-hydroxybenzotriazole monohydrate, and the reaction mixture was stirredfor 30 minutes at the same temperature. After this, 9.24 g of a 50%dimethylamine aqueous solution was added to the reaction solution, andthe reaction mixture was stirred for 1 hour while the temperature wasraised to room temperature. 150 mL of solvent was distilled off underreduced pressure, and to the residue thus obtained was added 100 mL ofchloroform and 100 mL of a 10% potassium carbonate aqueous solution.After liquid separation, the aqueous layer was extracted withchloroform, and the combined organic layer was washed with saturatedbrine and then dried with magnesium sulfate, after which the dryingagent was filtered off and the solvent was distilled off under reducedpressure. The residue thus obtained was subjected to columnchromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1to 10/0; v/v) to obtain 20.5 g of the titled compound (colorless solid).

MS (ESI pos.) m/z: 283([M+Na]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.31& 1.39 (each-s, 9H), 1.93-2.10 (m, 1H), 2.40-2.71 (m, 1H), 2.81 & 2.83(each-s, 3H), 2.97 (s, 3H), 3.42-3.79 (m, 2H), 4.59-4.71 (m, 1H),5.10-5.37 (m, 1H)

Step 2-4: Synthesis of (4S)-4-fluoro-N,N-dimethyl-L-prolinamidetrifluoroacetate

18 mL of trifluoroacetic acid was added under ice cooling to a 60 mLchloroform solution of 5.98 g of the compound obtained in step 2-3, andthe reaction mixture was stirred for 2 hours at the same temperature.After this, the solvent was distilled off under reduced pressure toobtain 12.1 g of residue (colorless oily substance). This compound wasused in the following reaction without being purified.

MS (ESI pos.) m/z: 161([M+H]⁺), 183([M+Na]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 2.12-2.30 (m, 1H), 2.68-3.02 (m, 1H), 2.93 (s, 3H), 2.98 (s, 3H),3.27-3.53 (m, 1H), 3.59-3.77 (m, 1H), 4.67-4.81 (m, 1H), 5.32-5.55 (m,1H), 8.83 (brs, 1H), 10.19 (brs, 1H)

Step 2-5: Synthesis of(4S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide

12.7 g of triethylamine was added under ice cooling to a chloroformsolution of 6.44 g of3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and thecompound obtained in step 2-4 (23.0 mmol, crude product), after whichthe reaction mixture was stirred for 24.5 hours at room temperature. Thereaction solution was poured into 200 mL of a 5% potassium carbonateaqueous solution under stirring, and extraction was performed withchloroform. The combined organic layer was washed with saturated brineand dried with magnesium sulfate, the drying agent was filtered off, andthe solvent was distilled off under reduced pressure to obtain 12.2 g ofresidue (Mars brown solid). The residue thus obtained was suspended in60 mL of a mixed solvent of chloroform and methanol (1:1; v/v), and theinsolubles were filtered off to obtain 3.64 g of the titled compound(isomer B; colorless powder). The filtrate was concentrated, and theresidue thus obtained was purified by column chromatography (first time:silica gel 60, mobile phase: ethyl acetate/n-hexane=1/3 to 10/0, v/v;second time: Chromatorex NH, mobile phase: chloroform/methanol=13/1,v/v) to obtain 340 mg of the titled compound (isomer A, colorlesspowder).

Isomer A: [α]_(D) ²⁹=+32° (c=0.224, methanol) MS (ESI pos.) m/z:454([M+Na]⁺), (ESI neg.) m/z: 430([M−H]⁻) ¹H-NMR (300 MHz, CDCl₃) δ(ppm); 2.03-2.24 (m, 1H), 2.60-2.95 (m, 1H), 2.70 (s, 3H), 3.23 (s, 3H),3.42-3.84 (m, 3H), 3.58 (s, 3H), 5.01-5.28 (m, 1H), 6.75 (d, J=8.2 Hz,1H), 6.79-6.91 (m, 2H), 7.07-7.20 (m, 2H), 7.23-7.33 (m, 1H), 8.00 (d,J=7.5 Hz, 1H), 9.54 (brs, 1H)

Isomer B: [α]_(D) ²⁸=−198° (c=0.733, N,N-dimethylformamide) MS (ESIpos.) m/z: 454([M+Na]⁺), (ESI neg.) m/z: 430([M−H]⁻) ¹H-NMR (300 MHz,DMSO-d₆) δ (ppm); 1.67-1.84 (m, 1H), 2.20-3.55 (m, 3H), 2.56 (s, 3H),2.57 (s, 3H), 3.48 (s, 3H), 4.49-4.58 (m, 1H), 5.12-5.40 (m, 1H), 6.77(d, J=8.2 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.93 (dd, J=8.2, 1.1 Hz, 1H),6.97-7.05 (m, 1H), 7.18 (dd, J=8.3, 2.3 Hz, 1H), 7.23-7.31 (m, 1H),7.60-7.70 (m, 1H), 10.44 (brs, 1H)

Step 2-6: Synthesis of(4S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

1.50 g of the compound obtained in step 2-5 (isomer B) was used as thestarting raw material to obtain 1.70 g of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁶=−222° (c=0.654, chloroform) MS (ESI pos.) m/z: 654([M+Na]⁺)¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.74-1.92 (m, 1H), 1.97-2.23 (m, 1H),2.45 (s, 3H), 2.49-2.70 (m, 1H), 2.85 (s, 3H), 3.17-3.34 (m, 1H), 3.62(s, 3H), 3.67 (s, 3H), 3.88 (s, 3H), 4.30-4.59 (m, 1H), 4.69 (dd, J=9.6,3.7 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 6.63 (dd, J=8.9, 2.3 Hz, 1H), 6.77(dd, J=8.2, 0.9 Hz, 1H), 6.94-7.03 (m, 1H), 7.15-7.32 (m, 3H), 7.88-7.94(m, 2H), 8.15 (d, J=8.9 Hz, 1H)

EXAMPLE 3 Synthesis of1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4-difluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 3-1: Synthesis of 1-tert-butyl2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylate

150 g of 1-tert-butyl2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate, 264 g ofpyridinium chlorochromate, and 75 g of celite were stirred in 2 L ofchloroform at room temperature. During this stirring, another 100 g ofpyridinium chlorochromate was added, and the reaction mixture wasstirred for a total of 7 days. The reaction solution was filteredthrough celite (washed with 500 mL of chloroform), and the filtrate wasconcentrated under reduced pressure to obtain 197 g of black oil. Theresidue thus obtained was purified by column chromatography (silica gel60, mobile phase: ethyl acetate/n-hexane=2/1; v/v) to obtain 119 g ofthe titled compound (yellow oily substance).

MS (ESI neg.) m/z: 242([M−H]⁻) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.30-1.50 (m, 9H), 2.59 (dd, J=18.9, 2.6 Hz, 1H), 2.84-3.05 (m, 1H),3.77 (s, 3H), 3.86-4.03 (m, 2H), 4.67-4.92 (m, 1H)

Step 3-2: Synthesis of 1-tert-butyl2-methyl(2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate

36.0 g of [bis(2-methoxyethyl)amino]sulfur trifluoride was addeddropwise over a period of 5 minutes under ice cooling to a 150 mLchloroform solution of 18.0 g of the compound obtained in step 3-1,after which the reaction mixture was stirred for 19 hours at roomtemperature. The reaction solution was added dropwise over a period of10 minutes under ice cooling to 300 mL of a saturated potassiumcarbonate aqueous solution. After liquid separation, the aqueous layerwas extracted with chloroform (30 mL×2), and the combined organic layerwas washed with 30 mL of saturated brine and dried with magnesiumsulfate, and the drying agent was filtered off, after which the solventwas distilled off under reduced pressure. The residue thus obtained waspurified by column chromatography (silica gel 60, mobile phase: ethylacetate/n-hexane=1/4; v/v) to obtain 15.4 g of the titled compound(yellow oily substance).

MS (ESI pos.) m/z: 288([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.43 &1.46 (each-s, 9H), 2.36-2.56 (m, 1H), 2.58-2.82 (m, 1H), 3.69-3.92 (m,2H), 3.77 (s, 3H) 4.40-4.61 (m, 1H)

Step 3-3: Synthesis of 1-(tert-butoxycarbonyl)-4,4-difluoro-L-proline

40 mL of a 2 mol/L sodium hydroxide aqueous solution was added dropwiseover a period of 4 minutes under ice cooling to a 152 mL methanolsolution of 15.2 g of the compound obtained in step 3-2, after which thereaction mixture was stirred for 2.5 hours at the same temperature. Uponcompletion of the reaction, the methanol was distilled off under reducedpressure, 100 mL of chloroform was added to the aqueous layer thusobtained, and then 90 mL of 1 mol/L hydrochloric acid was added dropwiseover a period of 6 minutes under ice cooling. Once it was confirmed thatthe aqueous layer was acidic, liquid separation was performed, and theaqueous layer was extracted with chloroform (30 mL×2). The combinedorganic layer was washed with 50 mL of saturated brine and dried withmagnesium sulfate, then the drying agent was filtered off and thesolvent was distilled off under reduced pressure to obtain 14.1 g ofresidue (white solid). The residue thus obtained was crystallized fromdiisopropyl ether/n-hexane to obtain 12.6 g of the titled compound(colorless crystals).

MS (ESI neg.) m/z: 250([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.36 &1.41 (each-s, 9H), 2.31-2.53 (m, 1H), 2.69-3.02 (m, 1H), 3.59-3.86 (m,2H) 4.30-4.43 (m, 1H), 12.98 (brs, 1H)

Step 3-4: Synthesis oftert-butyl(2S)-2-[(dimethylamino)carbonyl]-4,4-difluoropyrrolidin-1-carboxylate

A 40 mL tetrahydrofuran solution of 4.00 g of the compound obtained instep 3-3 and 3.23 g of 1-hydroxybenzotriazole monohydrate was stirredfor 30 minutes under ice cooling. 3.66 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was thenadded, and the reaction mixture was stirred for 30 minutes at the sametemperature. 2.15 g of a 50% dimethylamine aqueous solution was added tothe reaction solution, after which the reaction mixture was stirred for1 hour at room temperature. 60 mL of chloroform and 50 mL of a 5%potassium carbonate aqueous solution were added to the reactionsolution, liquid separation was performed, the aqueous layer wasextracted with chloroform (50 mL×2), the combined organic layer waswashed with 30 mL of saturated brine and then dried with magnesiumsulfate, and the drying agent was filtered off, after which the solventwas distilled off under reduced pressure. The residue thus obtained wassubjected to column chromatography (silica gel 60, mobile phase: ethylacetate/n-hexane=1/1 to 10/0; v/v) to obtain 4.02 g of the titledcompound (colorless solid).

MS (ESI pos.) m/z: 301([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.41 &1.46 (each-s, 9H), 2.28-2.48 (m, 1H), 2.55-2.73 (m, 1H), 2.99 & 3.00(each-s, 3H), 3.06 & 3.10 (each-s, 3H), 3.75-4.02 (m, 2H), 4.68-4.91 (m,1H)

Step 3-5: Synthesis of 4,4-difluoro-N,N-dimethyl-L-prolinamidetrifluoroacetate

11 mL of trifluoroacetic acid was added under ice cooling to a 40 mLchloroform solution of 3.85 g of the compound obtained in step 3-4, andthe reaction mixture was stirred for 2 hours at room temperature. Thesolvent was then distilled off under reduced pressure to obtain 8.02 gof residue (pale yellow oily substance). This compound was used in thefollowing reaction without being purified.

MS (ESI pos.) m/z: 179 ([M+H]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm);2.43-2.62 (m, 1H), 2.89-3.18 (m, 1H), 2.92 (s, 3H), 2.98 (s, 3H),3.65-3.88 (m, 2H), 4.97 (t, J=8.7 Hz, 1H)

Step 3-6: Synthesis of1-[5-(chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4,4-difluoro-N,N-dimethyl-L-prolinamide

7.64 g of triethylamine was added under ice cooling and a nitrogenatmosphere to a 40 mL chloroform solution of 3.88 g of3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and thecompound (unpurified) obtained in step 3-5, after which the reactionmixture was stirred for 15.5 hours at room temperature. The reactionsolution was poured into 50 mL of a 5% potassium carbonate aqueoussolution under stirring, and extraction was performed with chloroform(30 mL×2). The combined organic layer was washed with saturated brineand dried with magnesium sulfate, after which the drying agent wasfiltered off and the solvent was distilled off under reduced pressure toobtain 5.82 g of residue (Mars brown solid). This residue was separatedand purified by column chromatography (silica gel 60, mobile phase:first time: ethyl acetate, second time: ethyl acetate/n-hexane=4/1; v/v)to obtain two kinds of diastereoisomer of the titled compound in amountsof 2.23 g (isomer A: colorless powder) and 2.70 g (isomer B: colorlesspowder).

Isomer A: [α]_(D) ²⁹=+116° (c=0.425, chloroform) MS (ESI pos.) m/z:472([M+Na]⁺), (ESI neg.) m/z: 448([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.96-2.16 (m, 1H), 2.47-2.58 (m, 6H), 2.59-2.78 (m, 1H),3.24-3.53 (m, 1H), 3.49 (s, 3H), 3.72-3.99 (m, 2H), 6.54 (d, J=2.2 Hz,1H), 6.85 (d, J=8.2 Hz, 1H), 6.94 (dd, J=8.2, 0.9 Hz, 1H), 7.09-7.17 (m,1H), 7.20 (dd, J=8.3, 2.3 Hz, 1H), 7.26-7.35 (m, 1H), 8.05 (dd, J=7.7,1.6 Hz, 1H), 10.68 (s, 1H)

Isomer B: [α]_(D) ²⁸=159° (c=0.296, chloroform) MS (ESI pos.) m/z:472([M+Na]⁺), (ESI neg.) m/z: 448([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.94-2.13 (m, 1H), 2.36-2.53 (m, 6H), 2.68-2.93 (m, 1H),3.07-3.20 (m, 1H), 3.46 (s, 3H), 3.84-4.03 (m, 1H), 4.56-4.63 (m, 1H),6.77 (d, J=8.2 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.93 (dd, J=8.2, 1.1 Hz,1H), 7.02-7.10 (m, 1H), 7.20 (dd, J=8.4, 2.2 Hz, 1H), 7.25-7.33 (m, 1H),7.77 (dd, J=7.9, 1.8 Hz, 1H), 10.39 (s, 1H)

Step 3-7: Synthesis of1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4-difluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

1.94 g of the compound obtained in step 3-6 (isomer B) was used as thestarting raw material to obtain 2.31 g of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁸=−191° (c=0.595, chloroform) MS (ESI pos.) m/z: 672([M+Na]⁺)¹H-NMR (300 MHz, CDCl₃) δ (ppm); 2.06-3.88 (m, 7H), 2.41 (s, 3H), 2.76(s, 3H), 3.69 (s, 3H), 3.87 (s, 3H), 4.79-4.97 (m, 1H), 6.44 (d, J=2.3Hz, 1H), 6.58-6.63 (m, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.95-7.03 (m, 1H),7.03-7.11 (m, 1H), 7.20-7.30 (m, 2H), 7.81-7.88 (m, 1H), 7.92 (d, J=8.9Hz, 1H), 8.14 (d, J=8.9 Hz, 1H)

EXAMPLE 4 Synthesis ofmethyl(4S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate(diastereoisomer mixture) Step 4-1: Synthesis ofmethyl(4S)-4-fluoro-L-prolinate trfluoroacetate

1.5 g of the compound obtained in step 2-1 was used as the raw materialto obtain 2.56 g of the titled compound (yellow oily substance) by thesame method as in step 1-3.

MS (ESI pos.) m/z: 270 ([M+Na]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm);2.23-2.76 (m, 2H), 3.20-3.87 (m, 2H), 3.78 (s, 3H), 4.69 (dd, J=10.1,3.9 Hz, 1H), 5.32-5.64 (m, 1H).

Step 4-2: Synthesis ofmethyl(4S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate

2.79 g of triethylamine was added under ice cooling and a nitrogenatmosphere to a 50 mL chloroform solution of 1.70 g of3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 1.03 gof the compound obtained in step 4-1, after which the reaction mixturewas raised to room temperature and stirred for 13 hours at the sametemperature. The reaction solution was stirred while a 50 mL saturatedsodium hydrogencarbonate aqueous solution was added, and the reactionmixture was stirred for 15 minutes. After liquid separation, the aqueouslayer thus obtained was extracted with chloroform. The combined organiclayer was washed with saturated brine and dried with magnesium sulfate,after which the drying agent was filtered off and the solvent wasdistilled off under reduced pressure to obtain 2.54 g of residue(yellow, amorphous). The residue thus obtained purified by columnchromatography (silica gel 60, mobile phase: ethyl acetate), and stirredand washed in diisopropyl ether to obtain 1.98 g of a diastereoisomermixture of the titled compound (pale green, amorphous).

MS (ESI pos.) m/z: 441 ([M+Na]⁺), (ESI neg.) m/z: 417 ([M−H]⁻) ¹H-NMR(300 MHz, CDCl₃) δ (ppm); 2.14-5.34 (m, 12H), 6.71-8.31 (m, 8H)

Step 4-3: Synthesis ofmethyl(4S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate(diastereoisomer mixture)

1.00 g of the compound obtained in step 4-2 was used as the raw materialto obtain 1.31 g of the titled compound (diastereoisomer mixture;colorless, amorphous) by the same method as in step 1-5.

MS (ESI pos.) m/z: 641 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.47-5.01 (m, 18H), 6.42-8.22 (m, 10H)

EXAMPLE 5 Synthesis of tert-butyl1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate(levorotatory isomer) Step 5-1: Synthesis of 1-benzyl2-methyl(2S)-4-fluoropyrrolidine-1,2-dicarboxylate

5.11 g of a mixture (approximately 3:1) of1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise overa period of 10 minutes, and under ice cooling, to a suspension of 5.33 gof 1-benzyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate and962 mg of sodium fluoride in 53 mL of dichloromethane, after which thereaction mixture was stirred for 16 hours at room temperature. Afterthis, 100 mL of a 5% potassium carbonate aqueous solution was addedunder ice cooling to the reaction solution, and the reaction mixture wasstirred for 30 minutes at the same temperature. After liquid separation,the aqueous layer thus obtained was extracted with chloroform (30 mL×2),and the combined organic layer was washed with 50 mL of saturated brineand dried with magnesium sulfate, after which the drying agent wasfiltered off and the solvent was distilled off under reduced pressure.The residue thus obtained was subjected to column chromatography (silicagel 60, mobile phase: ethyl acetate/n-hexane=3/7; v/v) to obtain 1.50 gof the titled compound (colorless oil).

MS (ESI pos.) m/z: 304 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);2.00-2.26 (m, 1H), 2.37-2.71 (m, 1H), 3.48-3.80 (m, 4H), 3.83-4.09 (m,1H), 4.46-4.59 (m, 1H), 5.00-5.52 (m, 3H), 7.26-7.44 (m, 5H)

Step 5-2: Synthesis of 1-[(benzyloxy)carbonyl]-4-fluoro-L-proline

3.6 mL of a 2 mol/L sodium hydroxide aqueous solution was added underice cooling to a 15 mL methanol solution of 1.45 g of the compoundobtained in step 5-1, and the reaction mixture was stirred for 4 hoursat room temperature. The methanol was distilled off under reducedpressure, 30 mL of ethyl acetate was added, and the pH was adjusted to 2with 1 mol/L hydrochloric acid under ice cooling. After liquidseparation, the aqueous layer was extracted with ethyl acetate (10mL×2), the combined organic layer was washed with 10 mL of saturatedbrine and dried with magnesium sulfate, and the drying agent was thenfiltered off and the solvent was distilled off under reduced pressure toobtain 1.98 g of a pale yellow oil. The residue thus obtained wassubjected to column chromatography (silica gel 60, mobile phase: ethylacetate) to obtain 1.46 g of the titled compound (pale yellow oilysubstance).

MS (ESI pos.) m/z: 290 ([M+H]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);2.21-2.47 (m, 1H), 2.55-2.79 (m, 1H), 3.51-3.76 (m, 1H), 3.91-4.15 (m,1H), 4.41-4.65 (m, 1H), 5.08-5.36 (m, 3H), 6.89-7.47 (m, 6H)

Step 5-3: Synthesis of 1-benzyl2-tert-butyl(2S)-4-fluoropyrrolidine-1,2-dicarboxylate

A 28 mL t-butyl alcohol solution of 1.40 g of the compound obtained instep 5-2, 4.57 g of di-tert-butyl dicarbonate, and 192 mg of4-(dimethylamino)pyridine was stirred for 16 hours at room temperature.The reaction solution was concentrated under reduced pressure, afterwhich the residue thus obtained was purified by column chromatography(silica gel 60, mobile phase: ethyl acetate/n-hexane=1/4; v/v) to obtain1.35 g of the titled compound (colorless oily substance).

MS (ESI pos.) m/z: 346 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.29-1.51 (m, 9H), 1.96-2.23 (m, 1H), 2.51-2.71 (m, 1H), 3.55-3.76 (m,1H), 3.83-4.09 (m, 1H), 4.41 (q, J=8.3 Hz, 1H), 5.08-5.33 (m, 3H),7.24-7.40 (m, 5H)

Step 5-4: Synthesis of tert-butyl 4-fluoro-L-prolinate

1.25 g of the compound obtained in step 5-3 and 250 mg of 10%palladium-carbon were stirred for 1 hour at room temperature and under ahydrogen atmosphere in 12.5 mL of methanol. The insolubles were filteredoff and the filtrate was concentrated under reduced pressure to obtain704 mg of the titled compound (colorless oily substance).

MS (ESI pos.) m/z: 190 ([M+H]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.47(s, 9H), 1.86-2.18 (m, 2H), 2.31-2.49 (m, 1H), 3.10-3.29 (m, 2H), 3.90(t, J=7.9 Hz, 1H), 5.10-5.34 (m, 1H)

Step 5-5: Synthesis of tert-butyl1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate

2.09 g of triethylamine was added under ice cooling to an 11 mLchloroform solution of 1.06 g of3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 685 mgof the compound obtained in step 5-4 under a nitrogen atmosphere, afterwhich the reaction mixture was raised to room temperature and stirredfor 13 hours at that temperature. 10 mL of a 5% potassium carbonateaqueous solution was added to the reaction solution under stirring, andthe reaction mixture was stirred for 15 minutes. After liquidseparation, the aqueous layer thus obtained was extracted withchloroform. The combined organic layer was washed with saturated brineand dried with magnesium sulfate, then the drying agent was filtered offand the solvent was distilled off under reduced pressure to obtain 1.69g of residue (colorless, amorphous). The residue thus obtained wasseparated and purified by column chromatography (silica gel 60, mobilephase: ethyl acetate/n-hexane=2/3; v/v) to obtain two kinds ofdiastereoisomer of the titled compound in amounts of 678 mg (isomer A:colorless solid) and 839 mg (isomer B: colorless, amorphous).

Isomer A: [α]_(D) ²⁹=+75.7° (c=0.228 chloroform) MS (ESI pos.) m/z: 483([M+Na]⁺), (ESI neg.) m/z: 459 ([M−H]⁻) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.29 (s, 9H), 1.84-2.06 (m, 1H), 2.33-2.49 (m, 1H), 3.40-3.65 (m, 2H),3.56 (s, 3H), 3.95-4.11 (m, 1H), 5.02-5.26 (m, 1H), 6.73-6.84 (m, 3H),7.08-7.15 (m, 2H), 7.25-7.32 (m, 1H), 8.03 (s, 1H), 8.12 (dd, J=7.7, 1.8Hz, 1H)

Isomer B: [α]_(D) ²⁸=−169° (c=0.197, chloroform) MS (ESI pos.) m/z: 483([M+Na]⁺), (ESI neg.) m/z: 459 ([M−H]⁻) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.29 (s, 9H), 1.95-2.19 (m, 1H), 2.42-2.65 (m, 1H), 3.17-3.39 (m, 1H),3.49-3.70 (m, 1H), 3.58 (s, 3H), 4.10-4.23 (m, 1H), 5.14-5.39 (m, 1H),6.72 (d, J=8.2 Hz, 1H), 6.81 (dd, J=8.2, 1.0 Hz, 1H), 6.92 (d, J=2.0 Hz,1H), 7.01-7.09 (m, 1H), 7.14 (dd, J=8.2, 2.2 Hz, 1H), 7.23-7.39 (m, 2H),7.91 (dd, J=7.7, 1.8 Hz, 1H)

Step 5-6: Synthesis of tert-butyl1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate(levorotatory isomer)

300 mg of the compound obtained in step 5-5 (isomer B) was used as thestarting raw material to obtain 350 mg of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁸=−167° (c=0.209, chloroform) MS (ESI pos.) m/z: 683 ([M+Na]⁺)¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.33 (s, 9H), 1.47-3.95 (m, 7H), 3.69(s, 3H), 3.86 (s, 3H), 4.17-4.30 (m, 1H), 5.00-5.30 (m, 1H), 6.43 (d,J=2.2 Hz, 1H), 6.59 (dd, J=8.9, 2.3 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H),6.93-7.04 (m, 2H), 7.20-7.28 (m, 2H), 7.79 (dd, J=7.8, 1.6 Hz, 1H), 7.89(d, J=8.9 Hz, 1H), 8.17 (d, J=8.9 Hz, 1H)

EXAMPLE 6 Synthesis of1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-D-prolinamide(levorotatory isomer) Step 6-1: Synthesis oftert-butyl(2R,4R)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate

A 25 mL N,N-dimethylformamide solution of 2.50 g of(4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline and 2.19 g of1-hydroxybenzotriazole was stirred for 5 minutes under cooling, afterwhich 2.49 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride was added, and the reaction mixture was stirred for 30minutes at the same temperature. After this, 1.95 g of a 50%dimethylamine aqueous solution was added to the reaction solution, andthe reaction mixture was stirred for 16 hours at room temperature. Then100 mL of chloroform and 50 mL of a 5% potassium carbonate aqueoussolution were added to the reaction solution, and liquid separation wasperformed, after which the aqueous layer was extracted with chloroform(30 mL×2), and the combined organic layer was washed with 30 mL ofsaturated brine and dried with magnesium sulfate, then the drying agentwas then filtered off and the solvent was distilled off under reducedpressure. The residue thus obtained was subjected to columnchromatography (silica gel 60, mobile phase: ethyl acetate) to obtain2.74 g of the titled compound (pale yellow solid).

MS (ESI pos.) m/z: 281 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.39-1.48 (m, 9H), 1.95 (d, J=13.8 Hz, 1H), 2.17-2.34 (m, 1H), 2.88-3.29(m, 6H), 3.48-3.56 (m, 1H), 3.64-3.86 (m, 1H), 4.32 (q, J=4.8 Hz, 1H),4.66-4.83 (m, 1H)

Step 6-2: Synthesis oftert-butyl(2R)-2-[(dimethylamino)carbonyl]-4-fluoropyrrolidine-1-carboxylate

2.89 g of a mixture (approximately 3:1) of1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise overa period of 10 minutes, and under ice cooling, to a suspension of 2.64 gof the compound obtained in step 6-1 and 545 mg of sodium fluoride in 26mL of dichloromethane, after which the reaction mixture was stirred for16 hours at room temperature. After this, 100 mL of a 5% potassiumcarbonate aqueous solution was added under ice cooling to the reactionsolution, and the reaction mixture was stirred for 30 minutes at thesame temperature. After liquid separation, the aqueous layer thusobtained was extracted with chloroform (30 mL×2), and the combinedorganic layer was washed with 50 mL of saturated brine and dried withmagnesium sulfate, after which the drying agent was filtered off and thesolvent was distilled off under reduced pressure. The residue thusobtained was subjected to column chromatography (silica gel 60, mobilephase: ethyl acetate) to obtain 2.17 g of the titled compound (colorlesssolid).

MS (ESI pos.) m/z: 283 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.39-1.50 (m, 9H), 2.00-2.29 (m, 1H), 2.36-2.55 (m, 1H), 2.95-3.18 (m,6H), 3.58-3.98 (m, 2H), 4.71-4.90 (m, 1H), 5.12-5.36 (m, 1H)

Step 6-3: Synthesis of 4-fluoro-N,N-dimethyl-D-prolinamidetrifluoroacetate

10 mL of trifluoroacetic acid was added under ice cooling to a 30 mLchloroform solution of 2.09 g of the compound obtained in step 6-2,after which the reaction mixture was stirred for 2 hours at roomtemperature. The reaction mixture was then concentrated under reducedpressure, which gave 3.42 g of residue (pale yellow oily substance).This compound was used in the following reaction without being purified.

MS (ESI pos.) m/z: 161 ([M+H]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm);1.96-2.22 (m, 1H), 2.67-2.88 (m, 1H), 2.92 (s, 3H), 3.02 (s, 3H),3.38-3.66 (m, 2H), 4.74-4.88 (m, 1H), 5.36-5.61 (m, 1H), 8.84 (s, 1H),10.15 (s, 1H)

Step 6-4: Synthesis of1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-D-prolinamide

4.65 g of triethylamine was added under ice cooling and a nitrogenatmosphere to a 20 mL chloroform solution 2.36 g of3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the 3.30g of the compound obtained in step 6-3, after which the temperature wasraised to room temperature and the reaction mixture was stirred for 13hours that temperature. 10 mL of a 5% potassium carbonate aqueoussolution was added to the reaction solution under stirring, and thereaction mixture was stirred for 15 minutes. After liquid separation,the aqueous layer thus obtained was extracted with chloroform. Thecombined organic layer was washed with saturated brine and dried withmagnesium sulfate, then the drying agent was filtered off and thesolvent was distilled off under reduced pressure to obtain 3.94 g ofresidue (colorless, amorphous). The residue thus obtained was separatedand purified by column chromatography (silica gel 60, mobile phase:acetone/ethyl acetate=1/3 to 2/3; v/v), and each [part] was stirred andwashed in diisopropyl ether to obtain two kinds of diastereoisomer ofthe titled compound in amounts of 874 mg (isomer A: colorless solid) and1.80 g (isomer B: colorless solid).

Isomer A: [α]_(D) ²⁹=−128° (c=0.227, chloroform) MS (ESI pos.) m/z: 454([M+Na]⁺), (ESI neg.) m/z: 430 ([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.65-1.90 (m, 1H), 2.16-2.34 (m, 1H), 2.43-2.61 (m, 6H),3.22-3.34 (m, 1H), 3.32 (s, 3H), 3.77-3.96 (m, 2H), 5.05-5.29 (m, 1H),6.49 (d, J=2.3 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.92 (dd, J=8.2, 0.9 Hz,1H), 7.07-7.15 (m, 1H), 7.18 (dd, J=8.3, 2.3 Hz, 1H), 7.25-7.33 (m, 1H),8.05 (dd, J=7.8, 1.7 Hz, 1H), 10.51 (s, 1H)

Isomer B: [α]_(D) ²⁸=+188° (c=0.215, chloroform) MS (ESI pos.) m/z: 454([M+Na]⁺), (ESI neg.) m/z: 430 ([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.79-2.00 (m, 1H), 2.21-2.77 (m, 7H), 2.86-3.08 (m, 1H),3.38-3.85 (m, 1H), 3.46 (s, 3H), 4.57-4.69 (m, 1H), 5.18-5.43 (m, 1H),6.74 (d, J=8.2 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.89-6.94 (m, 1H),6.97-7.06 (m, 1H), 7.14-7.20 (m, 1H), 7.23-7.31 (m, 1H), 7.86 (dd,J=7.7, 1.6 Hz, 1H), 10.32 (s, 1H)

Step 6-5: Synthesis of1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-D-prolinamide(levorotatory isomer)

200 mg of the compound obtained in step 6-4 (isomer A) was used as thestarting raw material to obtain 272 mg of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁸=−129° (c=0.209, chloroform) MS (ESI pos.) m/z: 632 ([M+H]⁺)¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.77-2.02 (m, 1H), 2.12-2.29 (m, 1H),2.55 (s, 3H), 2.73 (s, 3H), 3.27 (s, 3H), 3.31-3.53 (m, 1H), 3.71-3.91(m, 1H), 3.79 (s, 3H), 3.87 (s, 3H), 4.05 (dd, J=9.6, 6.9 Hz, 1H),4.95-5.19 (m, 1H), 6.49 (d, J=2.2 Hz, 1H), 6.61 (dd, J=8.9, 2.3 Hz, 1H),6.73 (dd, J=8.1, 0.9 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 7.05-7.13 (m, 1H),7.21-7.29 (m, 2H), 7.91 (d, J=8.7 Hz, 1H), 8.15 (dd, J=7.8, 1.7 Hz, 1H),8.21 (d, J=8.9 Hz, 1H)

EXAMPLE 7 Synthesis of3-[(2S)-2-(azetidine-1-ylcarbonyl)-4-fluoropyrrolidin-1-yl]-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(levorotatory isomer) Step 7-1: Synthesis oftert-butyl(2S,4S)-2-(azetidin-1-ylcarbonyl)-4-hydroxypyrrolidine-1-carboxylate

2.19 g of 1-hydroxybenzotriazole monohydrate and 2.49 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedunder ice cooling to a 25 mL N,N-dimethylformamide solution of 2.50 g of(4S)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and stirred for 30minutes. 1.23 g of trimethyleneimine was added dropwise over a period of1 minute to the reaction mixture, and the reaction mixture was stirredfor 16 hours at room temperature. 30 mL of ethyl acetate and 20 mL of a5% potassium carbonate aqueous solution were added to the reactionsolution and stirred for 30 minutes. After liquid separation, theaqueous layer was extracted with ethyl acetate (50 mL×2), and thecombined organic layer was washed with water (50 mL×3) and 50 mL ofsaturated brine, and then dried with anhydrous magnesium sulfate, afterwhich the drying agent was filtered off, and the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel 60, mobile phase: ethyl acetate) to obtain2.81 g of the titled compound (pale yellow solid).

MS (ESI pos.) m/z: 293([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.44-1.51 (m, 9H), 1.92-2.01 (m, 1H), 2.13-2.43 (m, 3H), 3.42-3.52 (m,1H), 3.60-3.83 (m, 1H), 3.97-4.81 (m, 7H)

Step 7-2: Synthesis oftert-butyl(2S)-2-(azetidin-1-ylcarbonyl)-4-fluoropyrrolidine-1-carboxylate

2.68 g of a mixture (approximately 3:1) of1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise overa period of 10 minutes under ice cooling to a suspension of 2.71 g ofthe compound obtained in step 7-1 and 505 mg of sodium fluoride in 27 mLof dichloromethane, after which the reaction mixture was stirred for 16hours at room temperature. 100 mL of a 5% potassium carbonate aqueoussolution was added under ice cooling to the reaction solution, and thereaction mixture was stirred for 30 minutes at the same temperature.After liquid separation, the aqueous layer thus obtained was extractedwith chloroform (30 mL×2), and the combined organic layer was washedwith 50 mL of saturated brine and dried with magnesium sulfate, afterwhich the drying agent was filtered off and the solvent was distilledoff under reduced pressure. The residue thus obtained was subjected tocolumn chromatography (silica gel 60, mobile phase: ethyl acetate) toobtain 2.30 g of the titled compound (colorless oil).

MS (ESI pos.) m/z: 295([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.35-1.52 (m, 9H), 2.02-2.50 (m, 4H), 3.54-4.65 (m, 7H), 5.09-5.35 (m,1H)

Step 7-3: Synthesis of(2S)-2-(azetidin-1-ylcarbonyl)-4-fluoropyrrolidine trifluoroacetate

10 mL of trifluoroacetic acid was added under ice cooling to a 30 mLchloroform solution of 2.20 g of the compound obtained in step 7-2,after which the reaction mixture was stirred for 2 hours at roomtemperature. After this, the reaction mixture was concentrated underreduced pressure to obtain 3.82 g of residue (pale yellow oilysubstance). This compound was used in the following reaction withoutbeing purified.

MS (ESI pos.) m/z: 173([M+H]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm);1.97-2.36 (m, 3H), 2.48-2.75 (m, 1H), 3.37-3.66 (m, 2H), 3.89-4.07 (m,2H), 4.14-4.50 (m, 3H), 5.38-5.61 (m, 1H)

Step 7-4: Synthesis of3-[(2S)-2-(azetidin-1-ylcarbonyl)-4-fluoropyrrolidin-1-yl]-5-chloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

4.67 g of triethylamine was added under ice cooling and a nitrogenatmosphere to a 20 mL chloroform solution of 2.37 g of3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and thecompound (unpurified) obtained in step 7-3, after which the temperaturewas raised to room temperature and the reaction mixture was stirred for13 hours at that temperature. 10 mL of a 5% potassium carbonate aqueoussolution was added to the reaction solution under stirring, and thereaction mixture was stirred for 15 minutes. After liquid separation,the aqueous layer thus obtained was extracted with chloroform. Thecombined organic layer was washed with saturated brine and dried withmagnesium sulfate, then the drying agent was filtered off and thesolvent was distilled off under reduced pressure to obtain 4.02 g ofresidue (Mars brown solid). This was separated and purified by columnchromatography (silica gel 60, mobile phase: ethyl acetate/acetone=3/1to 1/1; v/v) to obtain two kinds of diastereoisomer of the titledcompound, which were stirred and washed with diisopropyl ether andobtained in amounts of 874 mg (isomer A: colorless solid) and 1.45 g(isomer B: colorless, amorphous).

Isomer A: [α]_(D) ²⁹=+168° (c=0.205, chloroform) MS (ESI pos.) m/z: 444([M+H]⁺), (ESI neg.) m/z: 442 ([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.67-2.30 (m, 4H), 3.13-3.73 (m, 5H), 3.48 (s, 3H), 3.78-4.02 (m,2H), 5.02-5.27 (m, 1H), 6.59 (d, J=2.2 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H),6.93 (dd, J=8.2, 1.1 Hz, 1H), 7.11 (dt, J=7.5, 1.2 Hz, 1H), 7.23-7.33(m, 2H), 7.98 (dd, J=7.6, 1.7 Hz, 1H), 10.54 (s, 1H)

Isomer B: [α]_(D) ²⁸=−137° (c=0.223, chloroform) MS (ESI pos.) m/z: 466([M+Na]⁺), (ESI neg.) m/z: 442 ([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.70-2.06 (m, 3H), 2.16-2.38 (m, 1H), 2.82-3.02 (m, 1H),3.05-3.15 (m, 1H), 3.41-3.72 (m, 3H), 3.48 (s, 3H), 3.74-3.86 (m, 1H),4.08-4.23 (m, 1H), 5.17-5.42 (m, 1H), 6.81-6.87 (m, 2H), 6.91-6.97 (m,1H), 7.02-7.09 (m, 1H), 7.22-7.34 (m, 2H), 7.83 (dd, J=7.8, 1.7 Hz, 1H),10.40 (s, 1H)

Step 7-5: Synthesis of3-[(2S)-2-(azetidin-1-ylcarbonyl)-4-fluoropyrrolidin-1-yl]-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(levorotatory isomer)

300 mg of the compound obtained in step 7-4 (isomer B) was used as thestarting raw material to obtain 353 mg of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁸=−204° (c=0.220, chloroform) MS (ESI pos.) m/z: 666 ([M+Na]⁺)¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.50-4.00 (m, 19H), 4.36-4.47 (m, 1H),5.13-5.41 (m, 1H), 6.42 (d, J=2.3 Hz, 1H), 6.60 (dd, J=8.9, 2.3 Hz, 1H),6.80-6.86 (m, 1H), 7.06-7.13 (m, 2H), 7.24-7.34 (m, 2H), 7.86 (dd,J=7.9, 1.6 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H)

EXAMPLE 8 Synthesis of1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-4-fluoro-L-prolinamide(levorotatory isomer) Step 8-1: Synthesis ofbenzyl(2S)-2-[(ethylamino)carbonyl]-4-fluoropyrrolidin-1-carboxylate

2.43 g of 1-hydroxybenzotriazole monohydrate and 2.75 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were addedunder ice cooling to a 32 mL N,N-dimethylformamide solution of 3.02 g ofthe compound obtained in step 5-2, and the reaction mixture was stirredfor 30 minutes. 1.16 g of a 70% ethylamine aqueous solution was added tothe reaction mixture. The reaction mixture was raised to roomtemperature and stirred for 14 hours. 50 mL of ethyl acetate and 30 mLof a 5% potassium carbonate aqueous solution were added to the reactionsolution, and the reaction mixture was stirred for 30 minutes at roomtemperature. After liquid separation, the aqueous layer was extractedwith chloroform (20 mL×2), the combined organic layer was washed withsaturated water (50 mL×2) and saturated brine (20 mL) and dried withmagnesium sulfate, the drying agent was filtered off, and the reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel 60, mobile phase: ethylacetate/n-hexane=7/3; v/v) to obtain 1.92 g of the titled compound(colorless solid).

MS (ESI pos.) m/z: 317 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);0.81-1.30 (m, 3H), 2.12-2.76 (m, 2H), 3.01-3.69 (m, 3H), 3.92-4.52 (m,2H), 4.97-5.35 (m, 3H), 5.62-6.80 (m, 1H), 7.23-7.45 (m, 5H)

Step 8-2: Synthesis of N-ethyl-4-fluoro-L-prolinamide

A suspension of 1.80 g of the compound obtained in step 8-1 and 360 mgof 10% palladium-carbon in 36 mL of methanol was stirred for 3 hours atroom temperature and under hydrogen atmosphere. The insolubles werefiltered off and the reaction mixture was concentrated under reducedpressure to obtain 1.07 g of the titled compound. This compound was usedin the following reaction without being purified.

MS (ESI pos.) m/z: 183 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.14(t, J=7.2 Hz, 3H), 1.93-2.18 (m, 1H), 2.26-2.87 (m, 3H), 3.17-3.38 (m,3H), 3.98 (q, J=8.6 Hz, 1H), 5.07-5.30 (m, 1H), 7.56 (s, 1H)

Step 8-3: Synthesis of1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-4-fluoro-L-prolinamide

1.0 mL of triethylamine was added under ice cooling to a 15 mLchloroform solution of 1.02 g of3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 530 mgof the compound obtained in step 8-2, after which the reaction mixturewas stirred for 18.5 hours at room temperature. 20 mL of a 5% potassiumcarbonate aqueous solution was poured into the reaction solution understirring, and extraction was performed with chloroform (20 mL×2). Thecombined organic layer was washed with saturated brine and dried withsodium sulfate, then the drying agent was filtered off and the solventwas distilled off under reduced pressure. The residue thus obtained wasseparated and purified by column chromatography (silica gel 60, mobilephase: ethyl acetate/acetone=98/2; v/v) to obtain two kinds ofdiastereoisomer of the titled compound in amounts of 708 mg (isomer A:colorless, amorphous) and 501 mg (isomer B: colorless, amorphous).

Isomer A: [α]_(D) ²⁵=−171° (c=0.200, chloroform) MS (ESI pos.) m/z:432([M+H]⁺), (ESI pos.) m/z: 454([M+Na]⁺), (ESI neg.) m/z: 430([M−H]⁻)¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 0.85 (t, J=7.2 Hz, 3H), 1.86-2.06 (m,1H), 2.16-2.41 (m, 1H), 2.72-2.95 (m, 3H), 3.38-3.58 (m, 4H), 4.07 (dd,J=8.6, 4.5 Hz, 1H), 5.09-5.39 (m, 1H), 6.71-6.85 (m, 2H), 6.89-7.19 (m,3H), 7.21-7.32 (m, 1H), 7.39 (s, 1H), 7.76 (dd, J=7.7, 1.6 Hz, 1H),10.41 (s, 1H)

Isomer B: [α]_(D) ²⁵=+54° (c=0.224, chloroform) MS (ESI pos.) m/z:454([M+Na]⁺), (ESI neg.) m/z: 430([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 0.89-0.98 (t, J=7.0 Hz, 3H), 1.71-1.96 (m, 1H), 2.08-2.28 (m,1H), 2.80-2.94 (m, 2H), 3.20-3.55 (m, 5H), 3.74-3.91 (m, 1H), 4.98-5.25(m, 1H), 6.53 (d, J=2.2 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 6.92 (dd,J=8.2, 1.0 Hz, 1H), 7.06-7.15 (m, 2H), 7.25-7.35 (m, 1H), 7.47-7.55 (m,1H), 8.13 (dd, J=7.8, 1.7 Hz, 1H), 10.50 (s, 1H)

Step 8-4: Synthesis of1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-4-fluoro-L-prolinamide(levorotatory isomer)

200 mg of the compound obtained in step 8-3 (isomer A) was used as thestarting raw material to obtain 65 mg of the titled compound (colorless,amorphous) by the same method as in step 1-5.

[α]_(D) ²⁵=−199° (c=0.153, chloroform) MS (ESI pos.) m/z: 632([M+H]⁺),(ESI neg.) m/z: 630([M−H]⁻) ¹H-NMR (499 MHz, CDCl₃) δ (ppm); 0.78 (t,J=7.2 Hz, 3H), 1.96-2.92 (m, 5H), 3.18-3.35 (m, 1H), 3.54 (s, 3H), 3.68(s, 3H), 3.83-3.96 (m, 4H), 4.96-5.20 (m, 1H), 6.27-6.32 (m, 1H), 6.44(d, J=2.1 Hz, 1H), 6.62 (dd, J=9.0, 2.3 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H),6.94 (d, J=2.1 Hz, 1H), 6.98-7.03 (m, 1H), 7.19-7.28 (m, 2H), 7.71-7.75(m, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H)

EXAMPLE 9 Synthesis of(4R)-1-{3-(2,4-dimethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-5,6-dimethoxy-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer) Step 9-1: Synthesis of3-(2,4-dimethoxyphenyl)-3-hydroxy-5,6-dimethoxy-1,3-dihydro-2H-indol-2-one

293 mg of 60% sodium hydride was added under ice cooling and a nitrogengas flow to a suspension of 1.38 g of 5,6-dimethoxy-1H-indol-2,3-dionein 30 mL of tetrahydrofuran, and the reaction mixture was stirred for 1hour at the same temperature. A Grignard's reagent generated in 20 mL oftetrahydrofuran using 3.61 g of 2,4-dimethoxybromobenzene and 486 mg ofmagnesium was added dropwise over a period of 3 minutes to the reactionmixture under ice cooling, after which the reaction mixture was stirredfor 13 hours at room temperature. 20 mL of saturated aqueous ammoniumchloride and 40 mL of ethyl acetate were added to the reaction solution,and the reaction mixture was stirred for 30 minutes at room temperature.After liquid separation, the aqueous layer was extracted with ethylacetate (20 mL×2), the combined organic layer was washed with saturatedbrine and dried with magnesium sulfate, and the drying agent was thenfiltered off and the filtrate was concentrated under reduced pressure.The residue thus obtained was purified by column chromatography (silicagel 60, mobile phase: ethyl acetate) to obtain 1.37 g of the titledcompound (brown solid).

MS (ESI pos.) m/z: 368 ([M+Na]⁺) ¹H-NMR (300 MHz, DMSO-D₆) δ (ppm); 3.43(s, 3H), 3.55 (s, 3H), 3.75 (s, 6H), 6.16 (s, 1H), 6.40 (s, 1H), 6.44(d, J=2.3 Hz, 1H), 6.47 (s, 1H), 6.59 (dd, J=8.6, 2.3 Hz, 1H), 7.68 (d,J=8.6 Hz, 1H), 9.98 (s, 1H)

Step 9-2: Synthesis of (4R)-4-fluoro-N,N-dimethyl-L-prolinamide

15 mL of trifluoroacetic acid was added to a 50 mL chloroform solutionof 5.00 g of the compound obtained in step 1-2a or 1-2b, and thereaction mixture was stirred for 2 hours at room temperature. Thereaction solution was concentrated under reduced pressure, after which100 mL of chloroform was added to the residue thus obtained, and a 5%potassium carbonate aqueous solution was added under ice cooling untilthe aqueous layer turned basic. After liquid separation, the aqueouslayer was extracted with chloroform. The combined organic layer waswashed with 30 mL of saturated brine and dried with magnesium sulfate,the drying agent was filtered off, and the reaction mixture wasconcentrated under reduced pressure. The residue thus obtained waspurified by column chromatography (silica gel 60, mobile phase:chloroform/methanol/28% aqueous ammonia=10/1/0.1; v/v) to obtain 3.10 gof the titled compound (yellow oily substance).

MS (ESI pos.) m/z: 161 ([M+H]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.79-2.02 (m, 1H), 2.04-2.67 (m, 1H), 2.26-2.42 (m, 1H), 2.99 (s, 3H),3.06-3.25 (m, 1H), 3.07 (s, 3H), 3.37 (ddd, J=33.0, 13.3, 4.3 Hz, 1H),4.17 (dd, J=9.2, 6.7 Hz, 1H), 5.16-5.39 (m, 1H)

Step 9-3: Synthesis of(4R)-1-[3-(2,4-dimethoxyphenyl)-5,6-dimethoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(mixture of diastereoisomers)

362 mL of thionyl chloride was added at −78° C. and under a nitrogen gasflow to a 14 mL chloroform solution of 700 mg of the compound obtainedin step 9-1 and 240 mg of pyridine, and the reaction mixture was stirredfor 30 minutes at the same temperature. After this, a 5 mL chloroformsolution of 485 mg of the compound obtained in step 9-2 and 2.05 g oftriethylamine was added over a period of 2 minutes, after which thetemperature was raised to room temperature and the reaction mixture wasstirred for 15 hours at that temperature. 50 mL of ethyl acetate and 30mL of a 5% potassium carbonate aqueous solution were added to thereaction solution, and the reaction mixture was stirred for 5 minutes.After liquid separation, the aqueous layer was extracted with ethylacetate (30 mL×2), the combined organic layer was washed with saturatedbrine and dried with magnesium sulfate, the drying agent was filteredoff, and the reaction mixture was concentrated under reduced pressure.The residue thus obtained was purified by column chromatography (silicagel 60N, mobile phase: ethyl acetate/acetone=1/1; v/v) to obtain 697 mgof mixture of diastereoisomers of the titled compound (reddish-brown,amorphous).

MS (ESI pos.) m/z: 510 ([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);1.82-5.47 (m, 24H), 6.35-6.67 (m, 4H), 7.44-8.15 (m, 2H)

Step 9-4: Synthesis of(4R)-1-{3-(2,4-dimethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-5,6-dimethoxy-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer)

200 mg of the diastereoisomer mixture obtained in step 9-3 was addedunder ice cooling to a suspension of 18 mg of sodium hydride in 2 mL ofN,N-dimethylformamide under a nitrogen atmosphere, and the reactionmixture was stirred for 1 hour at the same temperature. 107 mg of2,4-dimethoxybenzenesulfonyl chloride was added and the reaction mixturewas stirred for 30 minutes at the same temperature, after which 30 mL ofethyl acetate and 20 mL of a 5% potassium carbonate aqueous solutionwere added, and the reaction mixture was stirred for 15 minutes at roomtemperature. After liquid separation, the aqueous layer was extractedwith ethyl acetate (20 mL×2), the combined organic layer was dried withmagnesium sulfate, the drying agent was filtered off, and the solventwas distilled off under reduced pressure to obtain 300 mg of residue(brown oily substance). The residue thus obtained was separated andpurified by column chromatography (silica gel 60N, mobile phase: ethylacetate/acetone=3/1; v/v) to obtain two kinds of diastereoisomer of thetitled compound in amounts of 30 mg (isomer A: reddish-brown, amorphous)and 27 mg (isomer B: reddish-brown, amorphous).

Isomer A: [α]_(D) ²⁸=−169° (c=0.111, chloroform) MS (ESI pos.) m/z: 710([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.85-5.44 (m, 9H), 2.38 (s,3H), 2.78 (s, 3H), 3.64 (s, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 3.86 (s,3H), 3.95 (s, 3H), 6.34 (d, J=2.3 Hz, 1H), 6.40-6.48 (m, 2H), 6.55-6.63(m, 2H), 7.62-7.69 (m, 2H), 8.16 (d, J=9.0 Hz, 1H)

Isomer B: [α]_(D) ²⁸=+177° (c=0.104, chloroform) MS (ESI pos.) m/z: 710([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.76-2.03 (m, 1H), 2.10-2.26(m, 1H), 2.53-2.56 (m, 3H), 2.63 (s, 3H), 3.22 (s, 3H), 3.31-3.52 (m,1H), 3.62-4.01 (m, 1H), 3.70 (s, 3H), 3.77 (s, 3H), 3.80 (s, 3H), 3.87(s, 3H), 3.95 (s, 3H), 4.08-4.16 (m, 1H), 4.97-5.20 (m, 1H), 6.29 (d,J=2.3 Hz, 1H), 6.41 (s, 1H), 6.49 (d, J=2.3 Hz, 1H), 6.56-6.65 (m, 2H),7.61 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H)

EXAMPLE 10 Synthesis of(4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 10-1: Synthesis of5-chloro-3-hydroxy-3-(2-isopropylphenyl)-1,3-dihydro-2H-indol-2-one

Several drops of a 12 mL tetrahydrofuran solution of 8.2 g of1-bromo-2-isopropylbenzene were added to a 5 mL tetrahydrofuran solutionof 1.2 g of magnesium under a nitrogen atmosphere to initiate thereaction, after which the rest was gradually added drop-wise at a rateat which heating reflux was maintained. Upon completion of the dropping,the reaction mixture was refluxed for 0.5 hour in an oil bath, and thencooled to room temperature. A reagent prepared as above was graduallyadded drop-wise under ice cooling and a nitrogen atmosphere to asuspension of 3 g of 5-chloro-1H-indol-2,3-dione in 22 mL oftetrahydrofuran. Upon completion of the dropping, the temperature wasraised to room temperature, and then the reaction mixture was stirredfor 2 hours at that temperature. A 3N hydrochloric acid aqueous solutionwas poured into the reaction solution, and extraction was performed withethyl acetate. The organic layer was washed with water and saturatedbrine and dried with magnesium sulfate, and the drying agent was thenfiltered off and the solvent was distilled off under reduced pressure.The residue was purified by column chromatography (silica gel 60, mobilephase: ethyl acetate/hexane=1/2; v/v) to obtain 4.9 g of the titledcompound (pale yellow, amorphous).

MS (ESI pos.) m/z: 302([M+H]⁺, 324([M+Na]⁺), (ESI neg.) m/z: 300([M−H]⁻)¹H-NMR (300 MHz, CDCl₃) δ (ppm); 0.71 (d, J=6.7 Hz, 3H), 1.13 (d, J=6.7Hz, 3H), 2.31-2.66 (m, 1H), 3.94 (s, 1H), 6.73 (d, J=8.1 Hz, 1H), 7.00(d, J=8.1 Hz, 1H), 7.16 (dd, J=8.4, 2.2 Hz, 1H), 7.21-7.46 (m, 1H), 7.87(d, J=2.2 Hz, 1H), 8.79 (s, 1H)

Step 10-2: Synthesis of(4R)-1-[5-chloro-3-(2-isopropylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide

0.6 mL of pyridine was added to a 15.6 mL chloroform solution of 1.5 gof the compound obtained in step 10-1, and a 1 mL chloroform solution of0.54 mL of thionyl chloride was added dropwise under ice cooling, afterwhich the reaction mixture was stirred for 1 hour at room temperature.Upon completion of the reaction, water was added and extraction wasperformed with chloroform. The organic layer was washed with saturatedbrine and dried with magnesium sulfate, after which the solvent wasdistilled off under reduced pressure. 3.5 mL of triethylamine was addedto a 25 mL chloroform solution of the residue and the compound obtainedin step 9-2, after which the reaction mixture was stirred for 60 hoursat room temperature. Water was added to the reaction solution,extraction was performed with chloroform, and the organic layer waswashed with saturated brine and dried with magnesium sulfate, afterwhich the solvent was distilled off under reduced pressure. The residuewas separated and purified by column chromatography (silica gel 60,mobile phase: methanol/chloroform=1/9; v/v, ethyl acetate) to obtain twokinds of diastereoisomer of the titled compound in amounts of 1.08 g(isomer A: colorless, amorphous) and 0.15 g (isomer B: colorless,amorphous).

Isomer A: [α]_(D) ²⁸=+110° (c=0.218 chloroform) MS (ESI pos.) m/z:444([M+H]⁺, 466([M+Na]⁺), (ESI neg.) m/z: 442([M−H]⁻) ¹H-NMR (300 MHz,DMSO-d₆) δ (ppm); 0.45 (d, J=6.5 Hz, 3H), 1.08 (d, J=6.7 Hz, 3H),2.18-2.42 (m, 2H), 2.46 (s, 3H), 2.57 (s, 3H), 3.18-3.51 (m, 1H),3.62-3.95 (m, 2H), 5.09-5.27 (m, 1H), 6.47 (s, 1H), 6.91 (d, J=8.2 Hz,1H), 7.10-7.49 (m, 4H), 8.11-8.60 (m, 1H), 10.87 (s, 1H)

Isomer B: [α]_(D) ²⁸=−136° (c=0.215, chloroform) MS (ESI pos.) m/z:444([M+H]⁺, 466([M+Na]⁺), (ESI neg.) m/z: 442([M−H]⁻) ¹H-NMR (300 MHz,DMSO-d₆) δ (ppm); 0.34-0.58 (m, 3H), 1.06 (d, J=6.5 Hz, 3H), 1.75-2.03(m, 1H), 2.31-2.64 (m, 5H), 2.87-3.23 (m, 1H), 3.43-3.74 (m, 1H),4.46-4.65 (m, 1H), 5.24-5.43 (m, 1H), 6.72-6.93 (m, 2H), 7.13-7.38 (m,4H), 7.99 (s, 1H), 10.62 (s, 1H)

Step 10-3: Synthesis of(4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-isopropylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

42 mg of the compound obtained in step 10-2 (isomer B) was used as thestarting raw material to obtain 32 mg of the titled compound (colorless,amorphous) by the same method as in step 1-5.

[α]_(D) ²⁸=−177° (c=0.100, chloroform) MS (ESI pos.) m/z: 644([M+H]⁺,666([M+Na]⁺, (ESI neg.) m/z: 642([M−H]⁻) ¹H-NMR (500 MHz, CDCl₃) δ(ppm); 0.34-0.84 (m, 6H), 1.66-2.81 (m, 11H), 3.26 (s, 1H), 3.60-3.94(m, 6H), 5.14-5.57 (m, 1H), 6.39-6.70 (m, 2H), 6.80-7.35 (m, 5H),7.82-8.32 (m, 3H)

EXAMPLE 11 Synthesis of(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-hydroxyphenyl)-2-oxo-1,2,3,5,6,7-hexahydrocyclopenta[f]indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 11-1: Synthesis of3-[2-(benzyloxy)phenyl]-3-hydroxy-3,5,6,7-tetrahydrocyclopenta[f]indol-2(1H)-one

Several drops of a 6 mL diethyl ether solution of 5.3 g of2-benzyloxybromobenzene were added to a suspension of 583 mg ofmagnesium in 2 mL of diethyl ether under a nitrogen atmosphere toinitiate the reaction, after which the rest was gradually added dropwiseat a rate at which heating reflux was maintained. Upon completion of thedropping, the reaction mixture was heated and refluxed for 2 hours in anoil bath, and then cooled to room temperature. A reagent prepared asabove was gradually added dropwise under ice cooling and a nitrogenatmosphere to an 11 mL tetrahydrofuran solution of 1.5 g of1,5,6,7-tetrahydrocyclopenta[f]indol-2,3-dione. Upon completion of thedropping, the temperature was raised to room temperature, and then thereaction mixture was stirred for 16 hours at that temperature. A 1 mol/Lhydrochloric acid aqueous solution was poured into the reactionsolution, and extraction was performed with ethyl acetate. The organiclayer was washed with water and saturated brine and dried with magnesiumsulfate, and the drying agent was then filtered off and the solvent wasdistilled off under reduced pressure. The residue was refined by columnchromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/2;v/v) to obtain 1.10 g of the titled compound (colorless powder).

MS (ESI pos.) m/z: 394([M+Na]⁺), (ESI neg.) m/z: 370([M−H]⁻) ¹H-NMR (300MHz, DMSO-d₆) δ (ppm); 1.90-2.05 (m, 2H), 2.70 (t, J=7.4 Hz, 2H), 2.81(t, J=7.5 Hz, 2H), 4.84 (s, 2H), 6.29 (s, 1H), 6.59 (d, J=9.0 Hz, 2H),6.82-6.92 (m, 3H), 6.97-7.04 (m, 1H), 7.14-7.24 (m, 4H), 7.86 (dd,J=7.7, 1.8 Hz, 1H), 10.04 (s, 1H)

Step 11-2: Synthesis of(4R)-1-{3-[2-(benzyloxy)phenyl]-2-oxo-1,2,3,5,6,7-hexahydrocyclopenta[f]indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

0.35 mL of pyridine was added to a 9 mL chloroform solution of 1.10 g ofthe compound obtained in step 11-1, and a 1 mL chloroform solution of0.31 mL of thionyl chloride was added dropwise under ice cooling, afterwhich the reaction mixture was stirred for 1 hour at room temperature.Upon completion of the reaction, the solvent was distilled off underreduced pressure. 4 mL of triethylamine was added under ice cooling to a10 mL chloroform solution of the residue and the compound obtained instep 9-2, after which the reaction mixture was stirred for 15 hours atroom temperature. Water was added to the reaction solution, extractionwas performed with chloroform, and the organic layer was washed withsaturated brine and dried with magnesium sulfate, after which thesolvent was distilled off under reduced pressure. The residue waspurified by column chromatography (silica gel 60, mobile phase:methanol/chloroform=1/9; v/v, ethyl acetate) to obtain 971 mg of thetitled compound (pale yellow, amorphous).

[α]_(D) ²⁸=−69° (c=0.210, chloroform) MS (ESI pos.) m/z: 514([M+H]⁺,536([M+Na]⁺), (ESI neg.) m/z: 512([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm); 1.82-2.05 (m, 3H), 2.16-2.91 (m, 3H), 2.32 (s, 3H), 2.63-2.73 (m,2H), 2.78 (t, J=7.2 Hz, 2H), 4.81-4.97 (m, 2H), 5.22-5.40 (m, 1H), 6.55(s, 1H), 6.66 (s, 3H), 6.79-7.07 (m, 4H), 7.09-7.26 (m, 4H), 7.88 (d,J=8.4 Hz, 2H), 9.99 (s, 1H)

Step 11-3: Synthesis of(4R)-1-{3-[2-(benzyloxy)phenyl]-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-1,2,3,5,6,7-hexahydrocyclopenta[f]indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

42 mg of the compound obtained in step 11-2 was used as the starting rawmaterial to obtain 32 mg of the titled compound (colorless, amorphous)by the same method as in step 1-5.

[α]_(D) ²⁸=−67° (c=0.236, chloroform) MS (ESI pos.) m/z: 714([M+H]⁺,736([M+Na]⁺) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.77-1.97 (m, 1H),1.98-3.10 (m, 4H), 2.00-2.14 (m, 2H), 2.34 (s, 3H), 2.44-2.56 (m, 3H),2.67-2.84 (m, 2H), 2.96 (t, J=7.3 Hz, 2H), 3.52 (s, 3H), 3.76 (s, 3H),4.39-4.96 (m, 2H), 5.19-5.38 (m, 1H), 6.46-6.78 (m, 6H), 6.88 (t, J=7.5Hz, 1H), 6.97-7.18 (m, 4H), 7.70 (s, 1H), 7.78 (s, 1H), 8.00 (d, J=9.0Hz, 1H)

Step 11-4: Synthesis of(4R)-1-[1-(2,4-dimethoxyphenyl)sulfonyl]-3-(2-hydroxyphenyl)-2-oxo-1,2,3,5,6,7-hexahydrocyclopenta[f]indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

10 mg of 20% palladium hydroxide (50% water content) was added to a 1 mLmethanol solution of 42 mg of the compound obtained in step 11-3, andthe reaction mixture was stirred for 75 minutes at room temperatureunder a hydrogen atmosphere. Upon completion of the reaction, thepalladium was filtered off with celite, and the filtrate wasconcentrated under reduced pressure. The residue thus obtained waspurified by column chromatography (silica gel 60, mobile phase: ethylacetate/hexane=3/1; v/v) to obtain 21 mg of the titled compound(colorless, amorphous).

[α]_(D) ²⁹=−203° (c=0.110, chloroform) MS (ESI pos.) m/z: 624([M+H]⁺,646([M+Na]⁺, (ESI neg.) m/z: 622([M−H]⁻) ¹H-NMR (500 MHz, MeOH-d₄) δ(ppm); 1.90-2.14 (m, 4H), 2.15-2.33 (m, 1H), 2.50-3.00 (m, 11H), 3.40(s, 3H), 3.46-3.64 (m, 1H), 3.84 (s, 3H), 5.15-5.26 (m, 1H), 6.51 (s,1H), 6.59-6.68 (m, 3H), 6.70-6.83 (m, 3H), 7.09 (t, J=7.8 Hz, 1H), 7.29(s, 1H), 7.70 (s, 1H), 7.98 (d, J=9.2 Hz, 1H)

EXAMPLE 12 Synthesis of(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 12-1: Synthesis of3-(2-fluorophenyl)-3-hydroxy-5-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one

16.8 mL of a hexane-cyclohexane solution of 1.0 mol/L sec-butyllithiumwas added dropwise under −78° C. cooling to a 15 mL tetrahydrofuransolution of 2 g of tert-butyl[4-(trifluoromethyl)phenyl]carbamate, andthe reaction mixture was stirred for 1 hour. The temperature was thenraised to −40° C., and the reaction mixture was stirred for 2.5 hours atthat temperature. The reaction mixture was cooled back down to −78° C.,a 7.5 mL tetrahydrofuran solution of 2.23 g ofethyl(2-fluorophenyl)(oxo)acetate was added dropwise, and the reactionmixture was stirred for 2 hours at the same temperature. The temperaturewas then raised to room temperature, and the reaction mixture wasstirred for 12 hours. A saturated ammonium chloride aqueous solution wasadded to the reaction solution, extraction was performed with ethylacetate, the organic layer was washed with saturated brine and driedwith magnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by column chromatography (silica gel60, mobile phase: ethyl acetate/hexane=1/1; v/v) to obtain 389 mg of thetitled compound (colorless powder).

MS (ESI pos.) m/z: 334([M+Na]⁺), (ESI neg.) m/z: 332([M−H]⁻) ¹H-NMR (300MHz, DMSO-d₆) δ (ppm); 7.01-7.13 (m, 2H), 7.18 (d, J=1.9 Hz, 1H),7.29-7.45 (m, 2H), 7.59-7.68 (m, 1H), 7.88-8.02 (m, 1H), 10.95 (s, 1H)

Step 12-2: Synthesis of(4R)-4-fluoro-1-[3-(2-fluorophenyl)-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-L-prolinamide(diastereoisomer mixture)

0.12 mL of pyridine was added to a 5 mL chloroform solution of 389 mg ofthe compound obtained in step 12-1, and a 1 mL chloroform solution of0.11 mL of thionyl chloride was added dropwise under ice cooling, afterwhich the reaction mixture was stirred for 0.5 hour at room temperature.0.87 mL of triethylamine and a 3 mL chloroform solution of 240 mg of thecompound obtained in step 9-2 were added under ice cooling to thisreaction solution, after which the reaction mixture was stirred for 10hours at room temperature. Water was added to the reaction solution,extraction was performed with chloroform, and the organic layer waswashed with saturated brine and dried with magnesium sulfate, afterwhich the solvent was distilled off under reduced pressure. The residuethus obtained was purified by column chromatography (silica gel 60,mobile phase: methanol/chloroform=1/99; v/v) to obtain 315 mg of adiastereoisomer mixture of the titled compound (colorless, amorphous).

MS (ESI pos.) m/z: 454([M+H]⁺, 476([M+Na]⁺), (ESI neg.) m/z: 452([M−H]⁻)¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.75-4.65 (m, 11H), 5.12-5.41 (m,1H), 6.89-8.15 (m, 7H), 10.88-11.10 (m, 1H)

Step 12-3: Synthesis of(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

100 mg of the compound obtained in step 12-2 was used as the startingraw material to obtain 32 mg of the titled compound (colorless,amorphous) by the same method as in step 1-5.

[α]_(D) ²⁸=−258° (c=0.102, chloroform) MS (ESI pos.) m/z: 654([M+H]⁺,676([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm); 1.93-2.19 (m, 1H),2.24-2.47 (m, 1H), 2.39 (s, 3H), 2.72 (s, 3H), 2.94-3.11 (m, 1H), 3.57(s, 3H), 3.59-3.81 (m, 1H), 3.88 (s, 3H), 4.61 (dd, J=8.8, 4.6 Hz, 1H),5.18-5.36 (m, 1H), 6.44 (d, J=2.2 Hz, 1H), 6.60 (dd, J=8.9, 2.3 Hz, 1H),6.71-6.84 (m, 1H), 7.14-7.32 (m, 3H), 7.60 (dd, J=8.7, 2.0 Hz, 1H),7.91-8.02 (m, 1H), 8.12-8.23 (m, 2H)

EXAMPLE 13 Synthesis of(4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-3-[2-(trifluoromethoxy)phenyl]-6-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 13-1: Synthesis of5-chloro-3-hydroxy-3-[2-(trifluoromethoxy)phenyl]-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one

21 mL of a heptane solution of 1.6 mol/L tert-butyllithium was addeddropwise under −78° C. cooling to a 30 mL diethyl ether solution of 4.00g of tert-butyl[4-chloro-3-(trifluoromethyl)phenyl]carbamate, and thereaction mixture was stirred for 1 hour. The temperature was then raisedto −40° C., and the reaction mixture was stirred for 2.5 hours at thattemperature. The reaction mixture was cooled back down to −78° C., a 15mL tetrahydrofuran solution of 4.25 g of ethyloxo[2-(trifluoromethoxy)phenyl]acetate was added dropwise, and thereaction mixture was stirred for 2 hours at the same temperature. Thetemperature was then raised to room temperature, and the reactionmixture was stirred for 15 hours. A saturated ammonium chloride aqueoussolution was added to the reaction solution, extraction was performedwith ethyl acetate, the organic layer was washed with saturated brineand dried with magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by columnchromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/4;v/v) to obtain 3.57 g of the titled compound (colorless powder).

MS (ESI neg.) m/z: 410([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 7.20(s, 1H), 7.22-7.31 (m, 2H), 7.47-7.56 (m, 2H), 8.05-8.13 (m, 1H), 10.99(s, 1H)

Step 13-2: Synthesis of(4R)-1-[5-chloro-2-oxo-3-[2-(trifluoromethoxy)phenyl]-6-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide

0.12 mL of pyridine was added to a 3 mL chloroform solution of 500 mg ofthe compound obtained in step 13-1, and 1 mL of a chloroform solution of0.10 mL of thionyl chloride was added dropwise under ice cooling, afterwhich the reaction mixture was stirred for 1 hour. Upon completion ofthe reaction, water was added and extraction was performed withchloroform. The organic layer was washed with saturated brine and driedwith magnesium sulfate, and the solvent was distilled off under reducedpressure. 1.7 mL of triethylamine was added under ice cooling to a 4 mLchloroform solution of 1.45 mmol of a compound obtained by the sameprocedure as in step 9-2 and the residue obtained above, after which thereaction mixture was stirred for 12 hours at room temperature. Water wasadded to the reaction solution, extraction was performed withchloroform, the organic layer was washed with saturated brine and driedwith magnesium sulfate, and then the solvent was distilled off underreduced pressure. The residue was separated and purified by columnchromatography (silica gel 60, mobile phase: ethyl acetate/hexane=3/1;v/v) to obtain two kinds of diastereoisomer of the titled compound inamounts of 206 mg (isomer A: pale yellow, amorphous) and 174 mg (isomerB: pale yellow, amorphous).

Isomer A: [α]_(D) ²⁸=−19° (c=0.101 chloroform) MS (ESI pos.) m/z:554([M+H]⁺, 576([M+Na]⁺), (ESI neg.) m/z: 552([M−H]⁻) ¹H-NMR (300 MHz,DMSO-d₆) δ (ppm); 1.75-2.00 (m, 1H), 2.36-2.60 (m, 1H), 2.40 (s, 3H),2.56 (s, 3H), 3.09 (dd, J=20.9, 11.6 Hz, 1H), 3.57 (ddd, J=36.56, 12.0,3.7 Hz, 1H), 4.70 (dd, J=8.6, 4.8 Hz, 1H), 5.19-5.49 (m, 1H), 7.09 (s,1H), 7.21-7.31 (m, 1H), 7.37 (s, 1H), 7.49 (dd, J=6.1, 3.6 Hz, 2H), 8.15(dd, J=6.1, 3.4 Hz, 1H), 10.89 (s, 1H)

Isomer B: [α]_(D) ²⁸=+51° (c=0.109, methanol) MS (ESI pos.) m/z:554([M+H]⁺, 576([M+Na]⁺), (ESI neg.) m/z: 552([M−H]⁻) ¹H-NMR (300 MHz,DMSO-d₆) δ (ppm); 1.66-1.96 (m, 1H), 2.23-2.42 (m, 1H), 2.53 (s, 3H),2.55 (s, 3H), 3.27-3.51 (m, 1H), 3.71-3.92 (m, 2H), 5.12-5.30 (m, 1H),6.80 (s, 1H), 7.24 (s, 1H), 7.25-7.32 (m, 1H), 7.47-7.63 (m, 2H), 8.32(dd, J=7.7, 1.9 Hz, 1H), 11.13 (s, 1H)

Step 13-3: Synthesis of(4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-3-[2-(trifluoromethoxy)phenyl]-6-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

97 mg of the compound obtained in step 13-2 (isomer A) was used as thestarting raw material to obtain 113 mg of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁸=−151° (c=0.215, chloroform) MS (ESI pos.) m/z: 754([M+H]⁺,776([M+Na]⁺, (ESI neg.) m/z: 752([M−H]⁻) ¹H-NMR (300 MHz, CDCl₃) δ(ppm); 1.73-2.43 (m, 2H), 2.49 (s, 3H), 2.73 (s, 3H), 2.89 (s, 3H), 2.96(s, 3H), 3.37-3.67 (m, 1H), 3.95-4.32 (m, 2H), 5.10-5.28 (m, 1H), 7.02(s, 1H), 7.12-7.25 (m, 2H), 7.33-7.59 (m, 3H), 8.02 (s, 1H), 8.25 (s,1H), 8.45 (dd, J=7.7, 1.9 Hz, 1H)

EXAMPLE 14 Synthesis of(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 14-1: Synthesis of(4R)-4-fluoro-1-[3-(2-methoxyphenyl)-2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-L-prolinamide

0.7 mL of thionyl chloride was added under ice cooling to a 10 mLchloroform solution of 2.24 g of3-hydroxy-3-(2-methoxyphenyl)-5-(trifluoromethoxy)-1,3-dihydro-2H-indol-2-oneand 800 mg of pyridine. The reaction mixture was stirred for 2.5 hoursat the same temperature, after which the excess amounts of solvent andreagent were distilled off under reduced pressure. 22.1 g oftriethylamine was added under ice cooling to a 15 mL chloroform solutionof the residue thus obtained (without being isolated) and 6.57 mmol of(4R)-4-fluoro-N,N-dimethyl-L-prolinamide trifluoroacetate. The reactionmixture was stirred for 13.5 hours at room temperature, after which 20mL of a 5% potassium carbonate aqueous solution was poured into thereaction mixture, and extraction was performed with chloroform (20mL×3). The combined organic layer was washed with saturated brine anddried with sodium sulfate, after which the drying agent was filtered offand the solvent was distilled off under reduced pressure. The residuethus obtained was separated and purified by column chromatography(silica gel 60, mobile phase: ethyl acetate/acetone=25/1; v/v) to obtaintwo kinds of diastereoisomer of the titled compound in amounts of 761 mg(isomer A: colorless, amorphous) and 633 mg (isomer B: colorless,amorphous).

Isomer A: [α]_(D) ²⁵=+123° (c=0.291 chloroform) MS (ESI pos.) m/z:482([M+H]⁺), (ESI pos.) m/z: 504([M+Na]⁺), (ESI neg.) m/z: 480([M−H]⁻)¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.64-1.94 (m, 1H), 2.17-2.38 (m, 1H),2.42-2.58 (m, 5H), 3.24-3.50 (m, 5H), 3.74-3.95 (m, 2H), 5.04-5.32 (m,1H), 6.44 (d, J=1.7 Hz, 1H), 6.84-6.98 (m, 2H), 7.06-7.18 (m, 2H),7.24-7.35 (m, 1H), 8.04 (dd, J=7.6, 1.7 Hz, 1H), 10.58 (s, 1H) ¹H-NMR(300 MHz, CDCl₃) δ (ppm); 1.85-2.35 (m, 2H), 2.53 (s, 3H), 2.66 (s, 3H),3.49-3.73 (m, 4H), 4.03-4.21 (m, 2H), 5.05-5.32 (m, 1H), 6.75 (d, J=2.2Hz, 1H), 6.80-6.87 (m, 2H), 6.97-7.05 (m, 1H), 7.08-7.17 (m, 1H),7.25-7.32 (m, 1H), 8.23 (dd, J=7.8, 1.7 Hz, 1H), 9.43 (s, 1H)

Isomer B: [α]_(D) ²⁵=−172° (c=0.287, chloroform) MS (ESI pos.) m/z:504([M+Na]⁺), (ESI neg.) m/z: 480([M−H]⁻) ¹H-NMR (300 MHz, DMSO-D₆) δ(ppm); 1.82-2.02 (m, 1H), 2.26-2.56 (m, 7H), 2.84-3.09 (m, 1H),3.41-3.73 (m, 4H), 4.54-4.64 (m, 1H), 5.18-5.44 (m, 1H), 6.75-6.86 (m,2H), 6.92 (d, J=8.1 Hz, 1H), 6.98-7.01 (m, 1H), 7.11-7.20 (m, 1H),7.23-7.32 (m, 1H), 7.88 (dd, J=7.7, 1.3 Hz, 1H), 10.39 (s, 1H)

Step 14-2: Synthesis of(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

254 mg of the compound obtained in step 14-1 (isomer B) was used as thestarting raw material to obtain 242 mg of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁵=−215° (c=0.227, chloroform) MS (ESI pos.) m/z: 682([M+H]⁺),(ESI pos.) m/z: 704([M+Na]⁺), (ESI neg.) m/z: 680([M−H]⁻) ¹H-NMR (499MHz, CDCl₃) δ (ppm); 1.62-2.01 (m, 2H), 2.31 (s, 3H), 2.74 (s, 3H),2.98-3.78 (m, 8H), 3.85 (s, 3H), 4.78-5.08 (m, 1H), 5.20-5.37 (m, 1H),6.42 (d, J=2.1 Hz, 1H), 6.60 (dd, J=8.8, 2.4 Hz, 1H), 6.75-6.79 (m, 1H),6.92-6.98 (m, 2H), 7.13-7.17 (m, 1H), 7.21-7.26 (m, 1H), 7.72-7.82 (m,1H), 7.99 (d, J=9.1 Hz, 1H), 8.13-8.18 (m, 1H)

EXAMPLE 15 Synthesis of(4R)-1-[1-(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer) Step 15-1: Synthesis of(4R)-4-fluoro-1-[3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-L-prolinamide

0.7 mL of thionyl chloride was added under ice cooling to a 10 mLchloroform solution of 800 mg of pyridine and 1.78 g of3-hydroxy-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one, andthe reaction mixture was stirred for 1 hour at the same temperature,after which the excess amounts of solvent and reagent were distilled offunder reduced pressure. 20.0 g of triethylamine was added under icecooling to a 20 mL chloroform solution of the residue thus obtained(without being isolated) and 6.60 mmol of(4R)-4-fluoro-N,N-dimethyl-L-prolinamide trifluoroacetate. The reactionmixture was stirred for 14 hours at room temperature, after which 10 mLof a 5% potassium carbonate aqueous solution was poured into thereaction mixture, and extraction was performed with chloroform (20mL×3). The combined organic layer was washed with saturated brine anddried with sodium sulfate, after which the drying agent was filtered offand the solvent was distilled off under reduced pressure. The residuethus obtained was purified by column chromatography (silica gel 60,mobile phase: first time: ethyl acetate/methanol=98/2 to 1/1; v/v,second time: ethyl acetate/acetone=20/1 to 10/1; v/v) to obtain 1.30 gof the titled compound (mixture of two kinds of diastereoisomer;colorless solid).

MS (ESI pos.) m/z: 412([M+H]⁺), (ESI pos.) m/z: 434([M+Na]⁺), (ESI neg.)m/z: 410([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.52-4.76 (m, 17H),5.01-5.48 (m, 1H), 6.32-7.33 (m, 6H), 7.82-8.12 (m, 1H), 9.99-10.28 (m,1H)

Step 15-2: Synthesis of(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer)

620 mg of the compound obtained in step 15-1 (diastereoisomer mixture)was added under ice cooling and a nitrogen atmosphere to a 10 mLN,N-dimethylformamide solution of 67 mg of sodium hydride, and thereaction mixture was stirred for 40 minutes. After this, a 2 mLN,N-dimethylformamide solution of 400 mg of 2,4-dimethoxybenzenesulfonylchloride was added dropwise. The reaction mixture was stirred for 30minutes at the same temperature, after which 5 mL of ethyl acetate and10 mL of a 5% potassium carbonate aqueous solution were added, and thereaction mixture was stirred at room temperature overnight. Theprecipitated solids were filtered off and separated and purified bycolumn chromatography (silica gel 60, mobile phase: ethylacetate/acetone=99/1; v/v) to obtain two kinds of diastereoisomer of thetitled compound in amounts of 184 mg (isomer A: colorless, amorphous)and 256 mg (isomer B: colorless, amorphous).

Isomer A: [α]_(D) ²⁵=−225° (c=0.187, chloroform) MS (ESI pos.) m/z:612([M+H]⁺), (ESI pos.) m/z: 634([M+Na]⁺) ¹H-NMR (499 MHz, CDCl₃) δ(ppm); 1.53-1.62 (m, 1H), 1.85-1.98 (m, 1H), 2.18-2.32 (m, 7H), 2.75 (s,3H), 3.10-3.25 (m, 1H), 3.55-3.86 (m, 9H), 4.89-5.01 (br, 1H), 5.21-5.39(m, 1H), 6.40 (d, J=1.8 Hz, 1H), 6.58 (dd, J=9.0, 2.3 Hz, 1H), 6.76 (d,J=7.9 Hz, 1H), 6.85-6.97 (m, 2H), 7.07 (dd, J=8.5, 1.2 Hz, 1H),7.17-7.24 (m, 1H), 7.74-7.84 (m, 2H), 8.15 (d, J=8.8 Hz, 1H)

Isomer B: [α]_(D) ²⁵=+142° (c=0.240, chloroform) MS (ESI pos.) m/z:612([M+H]⁺), (ESI pos.) m/z: 634([M+Na]⁺) ¹H-NMR (499 MHz, CDCl₃) δ(ppm); 1.81-1.96 (m, 1H), 2.11-2.23 (m, 4H), 2.46 (s, 3H), 2.62 (s, 3H),3.24 (s, 3H), 3.36-3.49 (m, 1H), 3.73-3.87 (m, 7H), 4.06-4.11 (m, 1H),5.00-5.15 (m, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.60 (dd, J=9.0, 2.3 Hz, 1H),6.66-6.73 (m, 2H), 7.03-7.10 (m, 2H), 7.18-7.24 (m, 1H), 7.81 (d, J=8.2Hz, 1H), 8.15-8.25 (m, 2H)

EXAMPLE 16 Synthesis of(4R)-1-[4,5-dichloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-5-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer) Step 16-1: Synthesis of4,5-dichloro-3-hydroxy-3-(2-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one

A 10 mL tetrahydrofuran solution of 3.02 g of2-bromo-1-methoxy-4-methylbenzene was added dropwise under a nitrogenatmosphere to a suspension of 360 mg of magnesium in 10 mL oftetrahydrofuran, after which the reaction mixture was stirred for 30minutes under heating and reflux, and then allowed to stand and cool toroom temperature.

1.50 g of 4,5-dichloro-1H-indol-2,3-dione was added under ice coolingand a nitrogen atmosphere to a 40 mL tetrahydrofuran solution of 310 mgof sodium hydride, and the reaction mixture was stirred for 1 hour.After this, 20 mL of a previously prepared tetrahydrofuran solution ofbromo(2-methoxy-5-methylphenyl)magnesium was added dropwise over aperiod of 20 minutes, and the reaction mixture was stirred for 4.5 hoursat the same temperature, after which 50 mL of a saturated ammoniumchloride aqueous solution was added, and the reaction mixture wasstirred for 30 minutes at room temperature. After liquid separation, theaqueous layer was extracted with ethyl acetate (30 mL×3), the combinedorganic layer was washed with saturated brine and dried with sodiumsulfate, and the drying agent was then filtered off and the solvent wasdistilled off under reduced pressure. The residue thus obtained wasstirred and washed with isopropyl ether and the solids were filtered offto obtain 1.23 g of the titled compound (yellow solid).

MS (ESI pos.) m/z: 360([M+Na]⁺), (ESI neg.) m/z: 336([M−H]⁻) ¹H-NMR (200MHz, DMSO-d₆) δ (ppm); 2.31 (s, 3H), 3.38 (s, 3H), 6.64-6.87 (m, 3H),7.00-7.13 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 10.61(s, 1H)

Step 16-2: Synthesis of(4R)-1-[4,5-dichloro-3-(2-methoxy-5-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide

0.18 mL of thionyl chloride was added under ice cooling to a 5 mLchloroform solution of 300 mg of pyridine and 600 mg of the compoundobtained in step 16-1. The reaction mixture was stirred for 1 hour atthe same temperature, after which a 5 mL chloroform solution of 430 mgof the compound obtained in step 9-2 was added without being isolated,after which 20 mL of triethylamine was added dropwise under ice cooling.The reaction mixture was stirred for 88 hours at room temperature, afterwhich 10 mL of a 5% potassium carbonate aqueous solution was poured intothe reaction mixture, and extraction was performed with chloroform (20mL×3). The combined organic layer was washed with saturated brine anddried with sodium sulfate, and the drying agent was then filtered offand the solvent was distilled off under reduced pressure. The residuethus obtained was purified by column chromatography (silica gel 60,mobile phase: ethyl acetate) to obtain 640 mg of the titled compound(two kinds of diastereoisomer; beige, amorphous).

MS (ESI pos.) m/z: 480([M+H]⁺), (ESI pos.) m/z: 502([M+Na]⁺), (ESI neg.)m/z: 478([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.69-4.69 (m, 17H),5.04-5.50 (m, 1H), 6.71-6.84 (m, 2H), 7.01-7.13 (m, 1H), 7.35-7.47 (m,1H), 7.63-7.83 (m, 1H), 10.47-10.78 (m, 1H)

Step 16-3: Synthesis of(4R)-1-[4,5-dichloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-5-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer)

301 mg of the compound obtained in step 16-2 (diastereoisomer mixture)was added under ice cooling and a nitrogen atmosphere to a 3 mLtetrahydrofuran solution of 26 mg of sodium hydride, and the reactionmixture was stirred for 20 minutes. After this, a 2 mL tetrahydrofuransolution of 170 mg of 2,4-dimethoxybenzenesulfonyl chloride was addeddropwise, and the reaction mixture was stirred for 2 hours at roomtemperature. Then 5 mL of ethylacetate and 10 mL of a 5% potassiumcarbonate aqueous solution were added and the reaction mixture wasstirred for 30 minutes at room temperature. After liquid separation, theaqueous layer was extracted with ethyl acetate (10 mL×3), and thecombined organic layer was dried with sodium sulfate, after which thedrying agent was filtered off and the solvent was distilled off underreduced pressure. The residue thus obtained was separated and purifiedby column chromatography (silica gel 60, mobile phase: ethylacetate/acetone=99/1; v/v) to obtain two kinds of diastereoisomer of thetitled compound in amounts of 115 mg (isomer A: colorless, amorphous)and 127 mg (isomer B: colorless, amorphous).

Isomer A: [α]_(D) ²⁵=−248° (c=0.183, chloroform) MS (ESI pos.) m/z:680([M+H]⁺), (ESI pos.) m/z: 702([M+Na]⁺ ¹H-NMR (499 MHz, CDCl₃) δ(ppm); 1.89 (s, 1H), 2.19-3.94 (m, 21H), 4.65-5.06 (m, 1H), 5.23-5.44(m, 1H), 6.43 (s, 1H), 6.57 (dd, J=9.0, 2.3 Hz, 2H), 6.97-7.05 (m, 1H),7.42 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.93 (d, J=8.5. Hz, 1H), 8.09-8.20(m, 1H)

Isomer B: [α]_(D) ²⁵=+211° (c=0.200, chloroform) MS (ESI pos.) m/z:680([M+H]⁺), (ESI pos.) m/z: 702([M+Na]⁺) ¹H-NMR (499 MHz, CDCl₃) δ(ppm); 1.88-2.23 (m, 2H), 2.33 (s, 3H), 2.55-2.81 (m, 6H), 3.36 (s, 3H),3.47-3.63 (m, 1H), 3.79-3.88 (m, 7H), 4.07-4.19 (m, 1H), 4.95-5.19 (m,1H), 6.48 (d, J=2.1 Hz, 1H), 6.57 (dd, J=8.8, 2.1 Hz, 1H), 6.63 (d,J=8.2 Hz, 1H), 6.99-7.07 (m, 1H), 7.41-7.48 (m, 1H), 7.67 (s, 1H),7.92-8.01 (m, 1H), 8.13 (d, J=8.8 Hz, 1H)

EXAMPLE 17 Synthesis of(4R)-1-{5-chloro-3-(5-chloro-2-methoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-4-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 17-1: Synthesis of5-chloro-3-(5-chloro-2-methoxyphenyl)-3-hydroxy-4-methyl-1,3-dihydro-2H-indol-2-one

A 5 mL tetrahydrofuran solution of 4.75 g of2-bromo-4-chloro-1-methoxybenzene was added dropwise under a nitrogenatmosphere to a suspension of 500 mg of magnesium in 10 mL oftetrahydrofuran, after which the reaction mixture was stirred whilebeing heated and refluxed for 30 minutes, and then allowed to stand andcool to room temperature.

1.96 g of 5-chloro-4-methyl-1H-indol-2,3-dione was added under icecooling and a nitrogen atmosphere to a 50 mL tetrahydrofuran solution of440 mg of sodium hydride, and the reaction mixture was stirred for 1hour. After this, a previously prepared 15 mL tetrahydrofuran solutionof bromo(5-chloro-2-methoxyphenyl)magnesium was added dropwise over aperiod of 10 minutes. The reaction mixture was stirred for 3 hours atthe same temperature, after which 50 mL of a saturated ammonium chlorideaqueous solution was added, and the reaction mixture was stirred foranother 30 minutes at room temperature. After liquid separation, theaqueous layer was extracted with ethyl acetate (30 mL×3), and thecombined organic layer was washed with saturated brine and dried withsodium sulfate, and the drying agent was then filtered off and thesolvent was distilled off under reduced pressure. The residue thusobtained was stirred and washed with isopropyl ether, and the solidswere then filtered off to obtain 2.43 g of the titled compound (yellowsolid).

MS (ESI neg.) m/z: 336([M−H]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.87(s, 3H), 3.41 (s, 3H), 6.70 (dd, J=8.2, 0.4 Hz, 1H), 6.78 (s, 1H), 6.93(d, J=8.7 Hz, 1H), 7.25 (dd, J=8.2, 0.4 Hz, 1H), 7.35 (dd, J=8.7, 2.8Hz, 1H), 7.83 (d, J=2.8 Hz, 1H), 10.48 (s, 1H)

Step 17-2: Synthesis of(4R)-1-[5-chloro-3-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide

0.36 mL of thionyl chloride was added under ice cooling to a 10 mLchloroform solution of 420 mg of pyridine and 1.19 g of the compoundobtained in step 17-1. The reaction mixture was stirred for 2 hours atthe same temperature, after which the excess amounts of solvent andreagent were distilled off under reduced pressure. 3.60 g oftriethylamine was added under ice cooling to a 15 mL chloroform solutionof the residue thus obtained (without being isolated) and 3.53 mmol of(4R)-4-fluoro-N,N-dimethyl-L-prolinamide trifluoroacetate. The reactionmixture was stirred for 19 hours at room temperature, after which 20 mLof a 5% potassium carbonate aqueous solution was poured into thereaction mixture, and extraction was performed with chloroform (20mL×2). The combined organic layer was washed with saturated brine anddried with sodium sulfate, after which the drying agent was filtered offand the solvent was distilled off under reduced pressure. The residuethus obtained was separated and purified by column chromatography(silica gel 60, mobile phase: ethyl acetate/acetone=98/2; v/v) to obtaintwo kinds of diastereoisomer of the titled compound in amounts of 880 mg(isomer A: orange solid) and 465 mg (isomer B: orange solid).

Isomer A: [α]_(D) ²⁵=+205° (c=0.284 chloroform) MS (ESI pos.) m/z:480([M+H]⁺), (ESI pos.) m/z: 502([M+Na]⁺), (ESI neg.) m/z: 478([M−H]⁻)¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.63-1.92 (m, 4H), 2.18-2.43 (m, 4H),2.46-2.57 (m, 3H), 3.27-3.57 (m, 4H), 3.88-4.09 (m, 2H), 5.06-5.33 (m,1H), 6.70 (d, J=8.2 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.2 Hz,1H), 7.36 (dd, J=8.8, 2.8 Hz, 1H), 7.87 (d, J=2.8 Hz, 1H), 10.58 (s, 1H)

Isomer B: [α]_(D) ²⁵=−156° (c=0.175, chloroform) MS (ESI pos.) m/z:480([M+H]⁺), (ESI pos.) m/z: 502([M+Na]⁺), (ESI neg.) m/z: 478([M−H]⁻)¹H-NMR (300 MHz, DMSO-d₆) δ (ppm); 1.71-2.09 (m, 4H), 2.22-4.46 (m,13H), 5.18-5.53 (m, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H),7.19-7.39 (m, 2H), 7.91 (d, J=2.3 Hz, 1H), 10.36 (s, 1H)

Step 17-3: Synthesis of(4R)-1-{5-chloro-3-(5-chloro-2-methoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-4-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

258 mg of the compound obtained in step 17-2 (isomer B) was used as thestarting raw material to obtain 183 mg of the titled compound(colorless, amorphous) by the same method as in step 1-5.

[α]_(D) ²⁵=−249° (c=0.178, chloroform) MS (ESI pos.) m/z: 679([M+H]⁺)¹H-NMR (499 MHz, CDCl₃) δ (ppm); 1.77-1.94 (m, 1H), 2.10-2.69 (m, 7H),2.74-3.91 (m, 14H), 4.94 (br, 1H), 5.22-5.41 (m, 1H), 6.41 (s, 1H), 6.57(dd, J=8.8, 2.1 Hz, 1H), 6.63-6.76 (m, 1H), 7.18 (dd, J=8.7, 2.6 Hz,1H), 7.34 (d, J=8.8 Hz, 1H), 7.65-7.91 (m, 2H), 8.05-8.16 (m, 1H)

EXAMPLE 18 Synthesis of(4R)-1-{3-(1,3-benzodioxol-4-yl)-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer) Step 18-1: Synthesis of(4R)-1-[3-(1,3-benzodioxol-4-yl)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide

0.36 mL of thionyl chloride was added under ice cooling to a 10 mLchloroform solution of 420 mg of pyridine and 1.06 g of3-(1,3-benzodioxol-4-yl)-5-chloro-3-hydroxy-1,3-dihydro-2H-indol-2-one.The reaction mixture was stirred for 2 hours at the same temperature,after which the excess amounts of solvent and reagent were distilled offunder reduced pressure. 3.63 g of triethylamine was added under icecooling to a 15 mL chloroform solution of the residue thus obtained(without being isolated) and 3.53 mmol of(4R)-4-fluoro-N,N-dimethyl-L-prolinamide trifluoroacetate. The reactionmixture was stirred for 2.5 hours at room temperature, after which 10 mLof a 5% potassium carbonate aqueous solution was poured into thereaction mixture, and extraction was performed with chloroform (20mL×2). The combined organic layer was washed with saturated brine anddried with sodium sulfate, after which the drying agent was filtered offand the solvent was distilled off under reduced pressure. The residuethus obtained was purified by column chromatography (silica gel 60,mobile phase: ethyl acetate/acetone=98/2; v/v) to obtain 418 mg of thetitled compound (mixture of two kinds of diastereoisomer; yellow,amorphous).

MS (ESI pos.) m/z: 446([M+H]⁺), (ESI pos.) m/z: 468([M+Na]⁺), (ESI neg.)m/z: 444([M−H]⁻) ¹H-NMR (200 MHz, DMSO-d₆) δ (ppm); 1.65-4.87 (m, 11H),4.95-5.57 (m, 1H), 5.76-5.92 (m, 2H), 6.69-7.47 (m, 6H), 10.50-10.84 (m,1H)

Step 18-2: Synthesis of(4R)-1-{3-(1,3-benzodioxol-4-yl)-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer, dextrorotatory isomer)

353 mg of the compound obtained in step 18-1 (mixture ofdiastereoisomers) was added under ice cooling and a nitrogen atmosphereto a suspension of 35 mg of sodium hydride in 3 mL of tetrahydrofuran,and the reaction mixture was stirred for 20 minutes. After this, a 2 mLtetrahydrofuran solution of 219 mg of 2,4-dimethoxybenzenesulfonylchloride was added dropwise. The reaction mixture was stirred for 2hours at the same temperature, after which 5 mL of ethyl acetate and 10mL of a 5% potassium carbonate aqueous solution were added, and thereaction mixture was stirred for 30 minutes at room temperature. Afterliquid separation, the aqueous layer was extracted with ethyl acetate(10 mL×3), and the combined organic layer was dried with sodium sulfate,after which the drying agent was filtered off and the solvent wasdistilled off under reduced pressure. The residue thus obtained wasseparated and purified by column chromatography (silica gel 60, mobilephase: ethyl acetate) to obtain two kinds of diastereoisomer of thetitled compound in amounts of 191 mg (isomer A: colorless, amorphous)and 75 mg (isomer B: colorless, amorphous).

Isomer A: [α]_(D) ²⁵=−222° (c=0.176, chloroform) MS (ESI pos.) m/z:646([M+H]⁺), (ESI pos.) m/z: 668([M+Na]⁺) ¹H-NMR (499 MHz, CDCl₃) δ(ppm); 1.99-2.24 (m, 2H), 2.43 (s, 3H), 2.66-2.76 (m, 4H), 3.52-3.63 (m,4H), 3.86 (s, 3H), 4.77-4.82 (m, 1H), 5.14-5.30 (m, 1H), 5.51-5.63 (m,2H), 6.40 (d, J=2.1 Hz, 1H), 6.60 (dd, J=8.8, 2.4 Hz, 1H), 6.67-6.71 (m,1H), 6.73-6.79 (m, 1H), 7.07 (dd, J=8.2, 1.2 Hz, 1H), 7.28 (dd, J=8.8,2.4 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 8.18 (d,J=9.1 Hz, 1H)

Isomer B: [α]_(D) ²⁵=+157° (c=0.185, chloroform) MS (ESI pos.) m/z:668([M+Na]⁺) ¹H-NMR (499 MHz, CDCl₃) δ (ppm); 1.88-2.03 (m, 1H),2.22-2.33 (m, 1H), 2.55 (s, 3H), 2.70 (s, 3H), 3.40-3.53 (m, 1H), 3.57(s, 3H), 3.75-3.89 (m, 4H), 4.04 (dd, J=9.5, 6.7 Hz, 1H), 5.06-5.24 (m,2H), 5.41 (d, J=1.5 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 6.59 (dd, J=9.0,2.2 Hz, 1H), 6.69 (dd, J=7.9, 1.2 Hz, 1H), 6.83-6.91 (m, 1H), 7.07 (d,J=2.4 Hz, 1H), 7.28 (dd, J=8.8, 2.4 Hz, 1H), 7.51 (d, J=7.0 Hz, 1H),7.93 (d, J=8.8 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H)

EXAMPLE 19 Synthesis of(4R)-1-[5-chloro-1-[(2,4-dibutoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer) Step 19-1: Synthesis of 1,3-dibutoxybenzene

25.5 g of butyl bromide was added to a 150 mL acetone solution of 26.4 gof potassium carbonate and 10.0 g of resorcinol, after which thereaction mixture was stirred for 6 hours at 90° C. 100 mL of a saturatedammonium chloride aqueous solution was poured into the reaction solutionunder stirring, following by 30 minutes more stirring, after which thesolvent was distilled off under reduced pressure. 200 mL of water wasadded, after which extraction was performed with ethyl acetate (200mL×3). The organic layer was washed with saturated brine and dried withmagnesium sulfate, and the drying agent was then filtered off and thesolvent was distilled off under reduced pressure. The residue thusobtained was separated and purified by column chromatography (silica gel60, mobile phase: hexane/ethyl acetate=95/5 to 1/1; v/v) to obtain 11.0g of the titled compound (colorless oily substance).

MS (ESI pos.) m/z: 223([M+H]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);0.90-1.06 (m, 6H), 1.39-1.59 (m, 4H), 1.68-1.85 (m, 4H), 3.88-4.01 (m,4H), 6.43-6.53 (m, 3H), 7.09-7.20 (m, 1H)

Step 19-2: Synthesis of potassium 2,4-dibutoxybenzenesulfonate

1.4 mL of trimethylsilyl chlorosulfonate was added dropwise over aperiod of 10 minutes under ice cooling and a nitrogen atmosphere to a 10mL 1,2-dichloroethane solution of 2.00 g of the compound obtained instep 19-1. The reaction mixture was stirred for 10 minutes at the sametemperature, after which 5 mL of water and 5 mL of chloroform wereadded, and the reaction mixture was stirred for 5 more minutes.Extraction was performed with water (20 mL×3), after which 5 mL of a 1mol/L potassium hydroxide aqueous solution was added to the aqueouslayer. After 30 minutes of stirring, the solvent was distilled off underreduced pressure to obtain 4.02 g of the titled compound (colorlesssolid).

MS (ESI neg.) m/z: 301([M−K]⁻) ¹H-NMR (300 MHz, DMSO-d₆) δ (ppm);0.82-1.01 (m, 6H), 1.33-1.76 (m, 8H), 3.84-4.06 (m, 4H), 6.29-6.51 (m,2H), 7.58 (d, J=8.4 Hz, 1H)

Step 19-3: Synthesis of 2,4-butoxybenzenesulfonyl chloride

30.7 g of phosphoryl chloride was added under ice cooling and a nitrogenatmosphere to 3.90 g of the compound obtained in step 19-2, and thereaction mixture was stirred for 5.5 hours at 130° C. After cooling toroom temperature, the reaction mixture was poured into 200 mL of iceblock, and the mixture was stirred for 20 minutes, and then 50 mL ofdiethyl ether was added and the reaction mixture was stirred for another30 minutes. Extraction was performed with diethyl ether (50 mL×2), afterwhich the organic layer was washed with saturated brine and dried withmagnesium sulfate. The drying agent was then filtered off and thesolvent was distilled off under reduced pressure. The residue thusobtained was separated and purified by column chromatography (silica gel60, mobile phase: hexane/ethyl acetate=9/1; v/v) to obtain 1.53 g of thetitled compound (colorless solid).

MS (ESI pos.) m/z: 343([M+Na]⁺) ¹H-NMR (300 MHz, CDCl₃) δ (ppm);0.92-1.06 (m, 6H), 1.42-1.67 (m, 4H), 1.72-1.96 (m, 4H), 3.98-4.18 (m,4H), 6.44-6.56 (m, 2H), 7.86 (d, J=9.6 Hz, 1H)

Step 19-4: Synthesis of(4R)-1-[5-chloro-1-[(2,4-dibutoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer)

200 mg of the compound obtained in step 1-4 (isomer B) was added underice cooling to a suspension of 20 mg of sodium hydride in 3 mL oftetrahydrofuran, and the reaction mixture was stirred for 20 minutes.After this, 2 mL of a tetrahydrofuran solution of 160 mg of2,4-dibutoxybenzenesulfonyl chloride was added dropwise. The reactionmixture was stirred for 2 hours at the same temperature, after which 5mL of ethyl acetate and 10 mL of a 5% potassium carbonate aqueoussolution were added, and the reaction mixture was stirred for 30 minutesat room temperature. After liquid separation, the aqueous layer wasextracted with ethyl acetate (10 mL×3), and the combined organic layerwas dried with sodium sulfate, after which the drying agent was filteredoff and the solvent was distilled off under reduced pressure. Theresidue thus obtained was separated and purified by columnchromatography (silica gel 60, mobile phase: n-hexane/ethylacetate=65/35; v/v) to obtain 221 mg of the titled compound (colorless,amorphous).

[α]_(D) ²⁵=−220° (c=0.192, chloroform) MS (ESI pos.) m/z: 716([M+H]⁺),(ESI pos.) m/z: 738([M+Na]⁺) ¹H-NMR (499 MHz, CDCl₃) δ (ppm); 0.85 (t,J=7.2 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.16-1.94 (m, 10H), 2.18-2.40(m,4H), 2.76 (s, 3H), 3.15-4.05 (m, 8H), 4.86 (brs, 1H), 5.23-5.44 (m, 1H),6.39 (d, J=2.1 Hz, 1H), 6.56 (dd, J=8.8, 2.1 Hz, 1H), 6.76 (d, J=8.5 Hz,1H), 6.93 (t, J=7.6 Hz, 1H), 7.02-7.10 (m, 1H), 7.20-7.25 (m, 2H),7.68-7.75 (m, J=7.9 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 8.13 (d, J=9.1 Hz,1H)

Tables 1-1 and 1-2 show the structural formulas of the compounds of thepresent invention in Examples 1 to 19.

TABLE 1-1 Example Structual Formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

TEST EXAMPLE 1

V1b and V1a Receptor Binding Experiment

Preparation of crude membranes from tissues and a V1b and V1a receptorbinding experiment were conducted according to the method reported in J.Clin. Invest. 98, 2729-2738 (1996). Rat pituitary gland was used for theV1b receptor binding experiment, while a membrane preparation from ratliver tissue was used for the V1a receptor binding experiment. Thecompounds of Examples 1, 2, and 3 were used for the test compounds.

The rats were decapitated, and the pituitary gland and liver wereimmediately excised. The pituitary gland and liver tissue werehomogenized with a 20 vol/wet weight of 50 mmol/L Tris-hydrochloridebuffer (pH 7.4, containing 10 mmol/L magnesium chloride). The homogenatewas centrifuged for 5 minutes at 1500 rpm and 4° C. to remove the nucleiand tissue debris. The supernatant was centrifuged for 20 minutes at48,000×g and 4° C. The pellet was homogenized with a 50 mmol/LTris-hydrochloride buffer (pH 7.4, containing 10 mmol/L magnesiumchloride), and centrifuged for 20 minutes at 48,000×g and 4° C. Thepellet thus obtained was suspended in a 50 mmol/L Tris-hydrochloridebuffer (pH 7.4) containing 10 mmol/L magnesium chloride and 0.1% bovineserum albumin to give the protein concentration 600 μg/mL, and this wasused for the binding experiment as a crude membrane preparation. Thecrude membrane preparation (0.5 mL, 300 μg protein/assay) was incubatedfor 60 minutes at 25° C. with [³H]Arg-vasopressin (final concentration:0.4 nmol/L). Upon completion of the reaction, the reaction solution wasfiltrated over GF/C glass fiber filter paper that had been soaked for 2hours in 0.3% polyethyleneimine, using a cell harvester for a receptorbinding experiment. The glass fiber filter paper was thoroughly dried,after which a scintillator was added, and the radioactivity on thefilter paper was measured with a liquid scintillation counter. Theamount of binding in the presence of 5 μmol/L Arg-vasopressin wasregarded as the nonspecific binding, and the specific binding wasdetermined by subfracting nonspecific binding from the total binding,which is the binding in the absence of 5 μmol/L Arg-vasopressin. Thetest compound was dissolved in a 100% DMSO solution and added to themembrane preparation simultaneously with the [³H]Arg-vasopressin. TheIC50 value of the test compound was calculated from the inhibition curveat a concentration of 0.1 nmol/L to 1 μmol/L. The concentration of thecompounds which causes 50% inhibition discussed in Examples 1, 2, and 3was 1 to 100×10⁻⁹ mol/L for the V1b receptor, and was 10⁻⁸ to 10⁻⁶ mol/Lfor the V1a receptor.

TEST EXAMPLE 2

Measurement of Drug Concentration in Plasma and Brain following OralAdministration to Rats

The compound of Example 1 and compound A (WO01/55130, listed inEXEMPLE 1) were orally administered to Sprague-Dawley rats (male, 8weeks) at a dose of 5 mL/kg (10 mg/kg) as solutions (each compound wasdissolved with 0.03 mol/L HCl containing 5% Cremophor EL, andconcentration was prepared by 2 mg/ml).

Blood was collected from the tail vein at 1 and 2 hours afteradministration. Immediately the brain was excised, 20% homogenate wasprepared with distilled water, for assay sample. Similarly, 0.3 mL ofblood was collected from the tail vein at 2, 4, 8, and 24 hoursfollowing administration, and the plasma following centrifugation wasused as a sample.

The concentrations of the compound of Example 1 and compound A in plasmawere measured using liquid chromatography tandem mass spectrometry(LC/MS/MS). Specifically, 200 μL of acetonitrile was added to 50 μL ofplasma or brain homogenate, vortex mixed and centrifuged. The resultingsupernatant was put in a liquid chromatograph with an Agilent ZorbaxSB-C18 5 μm column (50 mm long, 2.1 mm in diameter). The elute was 0.1%acetic acid/acetonitrile containing 0.1% acetic acid. The MS/MSdetection were performed using a Sciex API3000 LC/MS/MS system with ESIfor ionization, in positive ions and MRM mode for monitoring. The m/z632→472 and m/z 630→472 were monitored for the compound of Example 1 andcompound A, respectively.

The concentration of plasma and brain at each sampling point and meanplasma levels after oral administration were shown in Table 2 and Table3, respectively.

The brain levels of the compound of Example 1, in which fluorine wasintroduced into the pyrrolidine ring, were higher than those of compoundA at 1 and 2 hours, and it was also confirmed that Example 1 exhibitedthe higher plasma levels after 2 hours compared with compound A.

TABLE 2 Drug concentration (units: ng/mL or ng/g) 1 hour 2 hoursCompound of plasma 440 219 Example 1 brain 35 11 Compound A plasma 30389 brain 7 ND (Values are given as average values of three examples. ND:below the quantification detection limit of 5 ng/mL.)

TABLE 3 Drug concentration in plasma (units: ng/mL) 2 hours 4 hours 8hours 24 hours Compound of 139 51 10 ND Example 1 Compound A 80 13 2 ND(Values are given as average values of three examples. ND: below thequantification detection limit of 1 ng/mL.)

INDUSTRIAL APPLICABILITY

The compound of the present invention has antagonistic activity againstan arginine-vasopressin V1b receptor and is useful in preventing ortreating diseases such as depression, anxiety, Alzheimer's disease,Parkinson's disease, Huntington's disease, eating disorders,hypertension, gastrointestinal diseases, drug dependence, epilepsy,cerebral infarction, cerebral ischemia, cerebral edema, head trauma,inflammation, immunological diseases, and alopecia, to a method formanufacturing this compound.

1. A 1,3-dihydro-2H-indol-2-one derivative expressed by Formula 1:

(wherein R₁ is a halogen atom, a C₁ to C₄ alkyl group, a C₁ to C₄ alkoxygroup, a trifluoromethyl group, or a trifluoromethoxy group, R₂ is ahydrogen atom, a halogen atom, a C₁ to C₄ alkyl group, a C₁ to C₄ alkoxygroup, or a trifluoromethyl group, or R₂ is in the 6-position of theindol-2-one and R₁ and R₂ join together to form a C₃ to C₆ alkylenegroup, R₃ is a halogen atom, a hydroxyl group, a C₁ to C₄ alkyl group, aC₁ to C₄ alkoxy group, or a trifluoromethoxy group, R₄ is a hydrogenatom, a halogen atom, a C₁ to C₄ alkyl group, or a C₁ to C₄ alkoxygroup, or R₄ is in the 3-position of the phenyl and R₃ and R₄ jointogether to form a methylenedioxy group, R₅ is a hydrogen atom or afluorine atom, R₆ is an ethylamino group, a dimethylamino group, anazetidin-1-yl group, or a C₁ to C₄ alkoxy group, R₇ is a C₁ to C₄ alkoxygroup, and R₈ is a C₁ to C₄ alkoxy group), or a pharmaceuticallyacceptable salt thereof.
 2. The 1,3-dihydro-2H-indol-2-one derivative orpharmaceutically acceptable salt thereof according to claim 1, whereinR₁ is a chlorine atom, a methyl group, a methoxy group, atrifluoromethyl group, or a trifluoromethoxy group, R₂ is a hydrogenatom, a chlorine atom, a methyl group, or a methoxy group, R₃ is afluorine atom or a methoxy group, R₄ is a hydrogen atom, a chlorineatom, a methyl group, or a methoxy group, or R₄ is in the 3-position ofthe phenyl and R₃ and R₄ join together to form a methylenedioxy group,R₅ is a hydrogen atom or a fluorine atom, R₆ is a dimethylamino group,an azetidin-1-yl group, or a methoxy group, R₇ is in the 2-position ofthe phenyl, and is a methoxy group, and R₈ is a methoxy group.
 3. The1,3-dihydro-2H-indol-2-one derivative or pharmaceutically acceptablesalt thereof according to claim 1, expressed by the Formula 1a:

(wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are the same as defined inclaim 1), in which the substituent in the 2-position of the pyrrolidinehas the (S) configuration.
 4. The 1,3-dihydro-2H-indol-2-one derivativeor pharmaceutically acceptable salt thereof according to claim 3, in theform of a levorotatory isomer.
 5. The 1,3-dihydro-2H-indol-2-onederivative according to claim 3, which is one of the compounds listedbelow:(4R)-1-[5-chloro-1-[2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);(4S)-1-[5-chloro-1-[2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4-difluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);methyl(4S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-L-prolinate(diastereoisomer mixture);3-[(2S)-2-azetidin-1-ylcarbonyl)-4-fluoropyrrolidin-1-yl]-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(levorotatory isomer);(4R)-1-{3-(2,4-dimethoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-5,6-dimethoxy-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-fluorophenyl)-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);(4R)-1-[1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);(4R)-1-[4,5-dichloro-1-[2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-5-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer);(4R)-1-{5-chloro-3-(5-chloro-2-methoxyphenyl)-1-[(2,4-dimethoxyphenyl)sulfonyl]-4-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer); and(4R)-1-{3-(1,3-benzodioxol-4-yl)-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-fluoro-N,N-dimethyl-L-prolinamide(levorotatory isomer).
 6. A method for manufacturing a1,3-dihydro-2H-indol-2-one derivative expressed by Formula 1:

(wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are the same as defined inclaim 1) by reacting a compound expressed by Formula 2:

(wherein R₁, R₂, R₃, R₄, R₅, and R₆ are the same as defined in claim 1)with a compound expressed by Formula 3:

(wherein R₇ and R₈ are the same as defined in claim 1, and Hal is ahalogen atom) in the presence of a base.
 7. A compound expressed byFormula 2:

(wherein R₁, R₂, R₃, R₄, R₅, and R₆ are the same as defined in claim 1),or a salt thereof.
 8. A pharmaceutical composition, containing as anactive ingredient the compound or pharmaceutically acceptable saltthereof according to claim 1.